Following the publication of the original article,1 the authors identified a minor error in Figure 1G, where the western blot image of the a-tubulin reference for SGC-R was inadvertently duplicated with that of BGC-R. We sincerely apologise for any confusion this may have caused. It is important to note that this error did not affect the overall results, as the cleavage of PARP1 and caspase-3 was appropriately supported by the levels of total PARP1 and caspase-3.
We have located the original western blot data for the a-tubulin reference for SGC-R and have made the necessary corrections to Figure 1G. Importantly, we assure readers that this erratum does not impact the conclusions or descriptions presented in the article.
1. Zhu, Y., Zhou, B., Hu, X., Ying, S., Zhou, Q., Xu, W., Feng, L., Hou, T., Wang, X., Zhu, L., & Jin, H. (2022, Jan). LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c-Myc mRNA stability. Clin Transl Med, 12(1), e703. https://doi.org/10.1002/ctm2.703
{"title":"Erratum for the Clinical and Translational Medicine ‘LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c-Myc mRNA stability’ by Yiran Zhu et al.","authors":"Yiran Zhu, Bingluo Zhou, Xinyang Hu, Shilong Ying, Qiyin Zhou, Wenxia Xu, Lifeng Feng, Tianlun Hou, Xian Wang, Liyuan Zhu, Hongchuan Jin","doi":"10.1002/ctm2.70106","DOIUrl":"10.1002/ctm2.70106","url":null,"abstract":"<p>Following the publication of the original article,<sup>1</sup> the authors identified a minor error in Figure 1G, where the western blot image of the a-tubulin reference for SGC-R was inadvertently duplicated with that of BGC-R. We sincerely apologise for any confusion this may have caused. It is important to note that this error did not affect the overall results, as the cleavage of PARP1 and caspase-3 was appropriately supported by the levels of total PARP1 and caspase-3.</p><p>We have located the original western blot data for the a-tubulin reference for SGC-R and have made the necessary corrections to Figure 1G. Importantly, we assure readers that this erratum does not impact the conclusions or descriptions presented in the article.</p><p>1. Zhu, Y., Zhou, B., Hu, X., Ying, S., Zhou, Q., Xu, W., Feng, L., Hou, T., Wang, X., Zhu, L., & Jin, H. (2022, Jan). LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c-Myc mRNA stability. <i>Clin Transl Med, 12</i>(1), e703. https://doi.org/10.1002/ctm2.703</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Dear Editor,</p><p>Attaining a deep molecular response (DMR) has emerged as a desirable therapeutic target in chronic myeloid leukaemia (CML) patients considered for treatment-free remission (TFR).<span><sup>1</sup></span> Switching to second-line therapy after failing to reach DMR with frontline imatinib has been recognized as an effective approach.<span><sup>2</sup></span> The optimal timing for switching to more potent tyrosine kinase inhibitors (TKIs) to achieve timely DMR remains controversial.<span><sup>3</sup></span> Myelofibrosis (MF) is associated with poor overall survival and a greater risk of disease progression in CML patients.<span><sup>4-6</sup></span> However, the associations between MF and DMR in CML patients initially treated with imatinib have not been extensively studied, and we aimed to fill this gap.</p><p>Our study involved 925 CML patients with bone marrow biopsies who initially received imatinib from 1 January 2010 to 1 August 2022 (Figure S1). MF was evaluated by experienced pathologists through bone marrow biopsies and graded from 0 to 3 based on the WHO grading system (Table S1).<span><sup>7</sup></span> In this study, patients with MF-1 or higher were classified as having MF as a crucial complication of CML. The demographic and clinical characteristics of the enrolled patients, categorized by MR4.5 status, are depicted in Figure 1A. Different MF grades were significantly associated with both overall survival (log-rank <i>p</i> = .015) and MR4.5-free survival (log-rank <i>p</i> < .001) (Figure S2). Patients who achieved MR4.5 had a significantly higher proportion of non-MF cases (81.26% vs. 63.99%, <i>p</i> < .001) (Figure 1B). A correlation heatmap of different variables revealed that the white blood cell (WBC) count had a moderate, significant negative correlation with haemoglobin (HGB) levels (<i>r</i> = -0.58) (Figure 1C).</p><p>The 925 subjects were allocated to a training set and a validation set following a 7:3 ratio using a random splitting method via the ‘Sample’ function in R to ensure unbiased and random patient selection. No significant differences were found between the two datasets (Table S1). The Kaplan-Meier (K-M) curves revealed that patients with MF at diagnosis had a greater probability of remaining MR4.5-free compared with those without MF (<i>p</i> < .001) (Figure 2A, a). Further analysis with a landmark at 18 months revealed that the inverse association was significant only after 18 months (<i>p</i> < .001) (Figure 2A, b). Considering that the intersection of two curves in the K-M analysis might decrease the statistical efficiency, we concurrently plotted the restricted mean survival time (RMST) at 5 years (Figure 2B). The 5-year RMST was 39.05 months in MF patients and 33.44 months in non-MF patients.</p><p>In the training cohort, univariate Cox regression revealed that WBC, HGB, platelet (PLT), MF and 3-month early molecular response (EMR) were risk factors for the incidence of M
{"title":"Myelofibrosis predicts deep molecular response 4.5 in chronic myeloid leukaemia patients initially treated with imatinib: An extensive, multicenter and retrospective study to develop a prognostic model","authors":"Tian Zeng, Xiudi Yang, Yi Wang, Dijiong Wu, Weiying Feng, Ying Lu, Xiaoqiong Zhu, Lirong Liu, Mei Zhou, Li Zhang, Yanping Shao, Honglan Qian, Feng Zhu, Yu Chen, Dan Cao, Li Huang, Xiaoning Feng, Lili Chen, Gang Zhang, Jing Le, Weiguo Zhu, Yongming Xia, Yanxia Han, Yongqing Jia, Guoyan Tian, Hui Zhou, Linjuan Xu, Xiufeng Yin, Qinli Tang, Yuefeng Zhang, Guoli Yao, Xianghua Lang, Kaifeng Zhang, Xiujie Zhou, Junbin Guo, Jinming Tu, Jianzhi Zhao, Gongqiang Wu, Huiqi Zhang, Xiao Wu, Qiulian Luo, Lihong Cao, Binbin Chu, Wei Jiang, Haiying Wu, Liansheng Huang, Meiwei Hu, Muqing He, Jingjing Zhu, Hongyan Tong, Jie Jin, Jian Huang","doi":"10.1002/ctm2.70101","DOIUrl":"https://doi.org/10.1002/ctm2.70101","url":null,"abstract":"<p>Dear Editor,</p><p>Attaining a deep molecular response (DMR) has emerged as a desirable therapeutic target in chronic myeloid leukaemia (CML) patients considered for treatment-free remission (TFR).<span><sup>1</sup></span> Switching to second-line therapy after failing to reach DMR with frontline imatinib has been recognized as an effective approach.<span><sup>2</sup></span> The optimal timing for switching to more potent tyrosine kinase inhibitors (TKIs) to achieve timely DMR remains controversial.<span><sup>3</sup></span> Myelofibrosis (MF) is associated with poor overall survival and a greater risk of disease progression in CML patients.<span><sup>4-6</sup></span> However, the associations between MF and DMR in CML patients initially treated with imatinib have not been extensively studied, and we aimed to fill this gap.</p><p>Our study involved 925 CML patients with bone marrow biopsies who initially received imatinib from 1 January 2010 to 1 August 2022 (Figure S1). MF was evaluated by experienced pathologists through bone marrow biopsies and graded from 0 to 3 based on the WHO grading system (Table S1).<span><sup>7</sup></span> In this study, patients with MF-1 or higher were classified as having MF as a crucial complication of CML. The demographic and clinical characteristics of the enrolled patients, categorized by MR4.5 status, are depicted in Figure 1A. Different MF grades were significantly associated with both overall survival (log-rank <i>p</i> = .015) and MR4.5-free survival (log-rank <i>p</i> < .001) (Figure S2). Patients who achieved MR4.5 had a significantly higher proportion of non-MF cases (81.26% vs. 63.99%, <i>p</i> < .001) (Figure 1B). A correlation heatmap of different variables revealed that the white blood cell (WBC) count had a moderate, significant negative correlation with haemoglobin (HGB) levels (<i>r</i> = -0.58) (Figure 1C).</p><p>The 925 subjects were allocated to a training set and a validation set following a 7:3 ratio using a random splitting method via the ‘Sample’ function in R to ensure unbiased and random patient selection. No significant differences were found between the two datasets (Table S1). The Kaplan-Meier (K-M) curves revealed that patients with MF at diagnosis had a greater probability of remaining MR4.5-free compared with those without MF (<i>p</i> < .001) (Figure 2A, a). Further analysis with a landmark at 18 months revealed that the inverse association was significant only after 18 months (<i>p</i> < .001) (Figure 2A, b). Considering that the intersection of two curves in the K-M analysis might decrease the statistical efficiency, we concurrently plotted the restricted mean survival time (RMST) at 5 years (Figure 2B). The 5-year RMST was 39.05 months in MF patients and 33.44 months in non-MF patients.</p><p>In the training cohort, univariate Cox regression revealed that WBC, HGB, platelet (PLT), MF and 3-month early molecular response (EMR) were risk factors for the incidence of M","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu-Fei Duan, Jia-Hao Dai, Ying-Qi Lu, Han Qiao, Na Liu
The profound impact of the microbiota on the initiation and progression of cancer has been a focus of attention. In recent years, many studies have shown that microbial metabolites serve as key hubs that connect the microbiome and cancer progression, but the underlying molecular mechanisms have not been fully elucidated. Multiple mechanisms that influence tumour development and therapy resistance, including disrupting cellular signalling pathways, triggering oxidative stress, inducing metabolic reprogramming and reshaping tumour immune microenvironment, are reviewed. Focusing on recent advancements in this field, this review also summarises the methodological framework of studies regarding microbial metabolites. In this review, we outline the current state of research on tumour-associated microbial metabolites and describe the challenges in future scientific research and clinical applications.
Key points
Metabolites derived from both gut and intratumoural microbiota play important roles in cancer initiation and progression.
The dual roles of microbial metabolites pose an obstacle for clinical translations.
Absolute quantification and tracing techniques of microbial metabolites are essential for addressing the gaps in studies on microbial metabolites.
Integrating microbial metabolomics with multi-omics transcends current research paradigms.
{"title":"Disentangling the molecular mystery of tumour–microbiota interactions: Microbial metabolites","authors":"Yu-Fei Duan, Jia-Hao Dai, Ying-Qi Lu, Han Qiao, Na Liu","doi":"10.1002/ctm2.70093","DOIUrl":"10.1002/ctm2.70093","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The profound impact of the microbiota on the initiation and progression of cancer has been a focus of attention. In recent years, many studies have shown that microbial metabolites serve as key hubs that connect the microbiome and cancer progression, but the underlying molecular mechanisms have not been fully elucidated. Multiple mechanisms that influence tumour development and therapy resistance, including disrupting cellular signalling pathways, triggering oxidative stress, inducing metabolic reprogramming and reshaping tumour immune microenvironment, are reviewed. Focusing on recent advancements in this field, this review also summarises the methodological framework of studies regarding microbial metabolites. In this review, we outline the current state of research on tumour-associated microbial metabolites and describe the challenges in future scientific research and clinical applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Metabolites derived from both gut and intratumoural microbiota play important roles in cancer initiation and progression.</li>\u0000 \u0000 <li>The dual roles of microbial metabolites pose an obstacle for clinical translations.</li>\u0000 \u0000 <li>Absolute quantification and tracing techniques of microbial metabolites are essential for addressing the gaps in studies on microbial metabolites.</li>\u0000 \u0000 <li>Integrating microbial metabolomics with multi-omics transcends current research paradigms.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div> <section> <h3> Background</h3> <p>Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6-methyladenosine (m<sup>6</sup>A) is known to be involved in tumourigenesis. However, the role of m<sup>6</sup>A in regulating T-cell function and enhancing anti-tumour immunity remains unexplored.</p> </section> <section> <h3> Methods</h3> <p>Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m<sup>6</sup>A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA-seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single-cell RNA-seq (scRNA-seq). Furthermore, in vitro and in vivo T-cell cytotoxicity killing assay and CRISPR Cas9-mediated m<sup>6</sup>A reader YTHDF1-3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m<sup>6</sup>A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells.</p> </section> <section> <h3> Results</h3> <p>We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T-cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti-tumour immune response, along with deletion of the m<sup>6</sup>A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)-I degradation. Remarkably, these anti-tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon-gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T-cell killing ability, and concurrently dampening the expression of exhaustion-related genes.</p> </section> <section> <h3> Conclusion</h3> <p>Targeting METTL3 enhances anti-tumour immunity by boosting T-cell cytotoxicity and reversing T-cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti-tumour defenses and overcome immune resistance.</p> </section>
{"title":"Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy","authors":"Kaixin Wu, Sa Li, Guangliang Hong, Hongzhi Dong, Tongke Tang, He Liu, Lingmei Jin, Siyuan Lin, Jingyun Ji, Mingli Hu, Shuntian Chen, Haoyuan Wu, Guanzheng Luo, Haoyuan Wu, Xiangqian Kong, Jiekai Chen, Jiangping He, Hongling Wu","doi":"10.1002/ctm2.70089","DOIUrl":"10.1002/ctm2.70089","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6-methyladenosine (m<sup>6</sup>A) is known to be involved in tumourigenesis. However, the role of m<sup>6</sup>A in regulating T-cell function and enhancing anti-tumour immunity remains unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m<sup>6</sup>A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA-seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single-cell RNA-seq (scRNA-seq). Furthermore, in vitro and in vivo T-cell cytotoxicity killing assay and CRISPR Cas9-mediated m<sup>6</sup>A reader YTHDF1-3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m<sup>6</sup>A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T-cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti-tumour immune response, along with deletion of the m<sup>6</sup>A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)-I degradation. Remarkably, these anti-tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon-gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T-cell killing ability, and concurrently dampening the expression of exhaustion-related genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Targeting METTL3 enhances anti-tumour immunity by boosting T-cell cytotoxicity and reversing T-cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti-tumour defenses and overcome immune resistance.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matt Lechner, Liam Masterson, Shiri Mermelstein, Jacklyn Liu, Umar Rehman, Michelle Chen, James O'Mahoney, F. Christopher Holsinger
<p>Both in the United States and the United Kingdom, with similar trends in continental Europe, the rates of male HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) have overtaken the incidence rates of cervical cancer in women. Persistent, oropharyngeal human papillomavirus (HPV) infection has been the major driver behind this rapid increase.<span><sup>1</sup></span> Despite these alarming numbers, the awareness of HPV has been extremely low, which may have implications on vaccine uptake. We conducted a survey of 4871 adults across the United States to ascertain the current levels of HPV awareness in relation to oropharyngeal cancer. The cohort was 49.9% female and 49.7% male, with patient age well distributed across the various age groups (see Supplemental Table 1). Regarding OPSCC risk, 43.3% and 78.5% identified alcohol and smoking as risk factors, respectively. 72.8%, 37.7%, 30.3% and 42.3% identified chewing tobacco, betel leaf, catechu/areca nut and marijuana use as additional risk factors, respectively.</p><p>Crucially, only one-third (31.3%) were aware that HPV is one of the most important risk factors of OPSCC. Indeed, only 62.3% of respondents had heard of HPV prior to taking the survey. Of these, 68.5% were aware that HPV can be sexually transmitted and 60.0% knew that it can be transmitted through oral sex. Of the entire cohort, less than two-thirds (62.7%) were aware that there is a vaccine against HPV.</p><p>Altogether, these results show that the awareness of HPV and its link to OPSCC is still limited in the United States, despite the introduction of gender-neutral vaccination and amid rapidly increasing rates of disease.</p><p>Indeed, it is expected that OPSCC rates will continue to rise over the next two decades. Several authors have attempted to assess the costs of OPSCC in the United States, using data from the early 2000s or based on a state-specific database. The most recent estimate of oropharyngeal cancer treatment cost in the United States was published by Wu et al.,<span><sup>2</sup></span> who used a large nationwide database (Truven MarketScan Commercial Claims and Encounter Database). They estimated that the average total lifetime treatment cost per newly diagnosed commercially insured patient would be $152 378 in 2015 prices, equivalent to $178 010 in 2020 prices (Medical Care Consumer Price Index, available from the US Bureau of Labor Statistics, 2020). The overall cost for OPSCC treatment in the United States was estimated by combining Wu et al.<span><sup>2</sup></span> treatment cost for commercially insured patients with the incidence rates of OPC<span><sup>3</sup></span> and the population projections (US Bureau, 2020), which gave a total direct cost of over $4.2 billion in 2020.</p><p>Broader societal costs of OPSCC were based on Pearce et al.<span><sup>4</sup></span> assessment of lost workplace productivity cost due to head and neck cancer in Ireland, equivalent to $311 926 per case diagnosed (in 20
{"title":"Oropharyngeal cancer: Lack of human papillomavirus awareness and economic burden in the United States","authors":"Matt Lechner, Liam Masterson, Shiri Mermelstein, Jacklyn Liu, Umar Rehman, Michelle Chen, James O'Mahoney, F. Christopher Holsinger","doi":"10.1002/ctm2.70062","DOIUrl":"10.1002/ctm2.70062","url":null,"abstract":"<p>Both in the United States and the United Kingdom, with similar trends in continental Europe, the rates of male HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) have overtaken the incidence rates of cervical cancer in women. Persistent, oropharyngeal human papillomavirus (HPV) infection has been the major driver behind this rapid increase.<span><sup>1</sup></span> Despite these alarming numbers, the awareness of HPV has been extremely low, which may have implications on vaccine uptake. We conducted a survey of 4871 adults across the United States to ascertain the current levels of HPV awareness in relation to oropharyngeal cancer. The cohort was 49.9% female and 49.7% male, with patient age well distributed across the various age groups (see Supplemental Table 1). Regarding OPSCC risk, 43.3% and 78.5% identified alcohol and smoking as risk factors, respectively. 72.8%, 37.7%, 30.3% and 42.3% identified chewing tobacco, betel leaf, catechu/areca nut and marijuana use as additional risk factors, respectively.</p><p>Crucially, only one-third (31.3%) were aware that HPV is one of the most important risk factors of OPSCC. Indeed, only 62.3% of respondents had heard of HPV prior to taking the survey. Of these, 68.5% were aware that HPV can be sexually transmitted and 60.0% knew that it can be transmitted through oral sex. Of the entire cohort, less than two-thirds (62.7%) were aware that there is a vaccine against HPV.</p><p>Altogether, these results show that the awareness of HPV and its link to OPSCC is still limited in the United States, despite the introduction of gender-neutral vaccination and amid rapidly increasing rates of disease.</p><p>Indeed, it is expected that OPSCC rates will continue to rise over the next two decades. Several authors have attempted to assess the costs of OPSCC in the United States, using data from the early 2000s or based on a state-specific database. The most recent estimate of oropharyngeal cancer treatment cost in the United States was published by Wu et al.,<span><sup>2</sup></span> who used a large nationwide database (Truven MarketScan Commercial Claims and Encounter Database). They estimated that the average total lifetime treatment cost per newly diagnosed commercially insured patient would be $152 378 in 2015 prices, equivalent to $178 010 in 2020 prices (Medical Care Consumer Price Index, available from the US Bureau of Labor Statistics, 2020). The overall cost for OPSCC treatment in the United States was estimated by combining Wu et al.<span><sup>2</sup></span> treatment cost for commercially insured patients with the incidence rates of OPC<span><sup>3</sup></span> and the population projections (US Bureau, 2020), which gave a total direct cost of over $4.2 billion in 2020.</p><p>Broader societal costs of OPSCC were based on Pearce et al.<span><sup>4</sup></span> assessment of lost workplace productivity cost due to head and neck cancer in Ireland, equivalent to $311 926 per case diagnosed (in 20","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The mammalian innate immune system engages germline-encoded pattern recognition receptors (PRRs) to sense the agonists from invading organisms to discriminate ‘self’ and ‘nonself’.<span><sup>1</sup></span> Those agonists are usually large molecular signatures termed pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs), such as bacterial lipopolysaccharide (LPS) and fungal <i>β-</i>glucan recognized by toll-like receptor 4 or dectin-1, respectively.<span><sup>2, 3</sup></span> Notably, several recent works revealed that, besides the molecular patterns, specific small molecules can also act as agonists that elicit innate immune responses efficiently.<span><sup>4</sup></span> Several <i>β-</i><span>d</span>-<i>manno</i>-heptose metabolites involved in the biosynthesis of LPSs have been identified as small molecule agonists that can be recognized by host alpha-protein kinase 1 (ALPK1), with ADP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (ADP-heptose) and its C-6′′ epimer as the most potent ones.<span><sup>5</sup></span> Upon binding to ADP-heptose, ALPK1 will undergo conformational changes to phosphorylate TRAF-interacting protein with forkhead-associated domain (TIFA), and then triggers the activation of Nuclear factor kappa B (NF-κB) and inflammation.</p><p>ADP-heptose is synthesized from <span>d</span>-sedoheptulose 7-phosphate (S7P) via a four-step relay catalyzed by NDP-<span>h</span>eptose <span>b</span>iosynthetic <span>e</span>nzymes (HBEs) with isomerase, kinase, phosphatase, and nucleotidyltransferase activities (Figure 1). Three types of <span>H</span>B<span>E</span>s with <span>n</span>ucleotidyltransfer<span>ase</span> (HENase) activities were identified, including monodomain nucleotidyltransferase, didomain kinase/nucleotidyltransferase, and tridomain isomerase/kinase/nucleotidyltransferase.<span><sup>6</sup></span> Before our work, knowledge of HBEs is limited to bacteria. We expanded the understanding of HBEs repertoire beyond the territory of bacteria to viruses, archaea, and eukaryotes.<span><sup>7</sup></span> Enzymatic characterization of HBEs from different kingdoms verified that all of them could synthesize ADP-heptose and some HENases could also recognize CTP and UTP to generate two new heptose metabolites, CDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (CDP-heptose) and UDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (UDP-heptose). Systematic evaluation of the NTP substrate scopes of HENases identified a conserved (F/L)XXG<b>R</b>STT motif (STT<sub>R5</sub>) as a hallmark of HENases with high NTP substrate promiscuity (Figure 1). The fifth arginine residue of the STT<sub>R5</sub> motif may stabilize NTP in a reactive conformation by contributing cation-π interaction with its nucleotide base and hydrogen bonds with its phosphate groups, thereby enabling the HENases to take different NTPs t
{"title":"NDP-β-d-manno-heptoses are small molecule agonists sensed by the vertebrates to discriminate organisms of different kingdoms","authors":"Yue Tang, Zijian Zhong, Huijin Mao, Yihua Chen","doi":"10.1002/ctm2.70103","DOIUrl":"10.1002/ctm2.70103","url":null,"abstract":"<p>The mammalian innate immune system engages germline-encoded pattern recognition receptors (PRRs) to sense the agonists from invading organisms to discriminate ‘self’ and ‘nonself’.<span><sup>1</sup></span> Those agonists are usually large molecular signatures termed pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs), such as bacterial lipopolysaccharide (LPS) and fungal <i>β-</i>glucan recognized by toll-like receptor 4 or dectin-1, respectively.<span><sup>2, 3</sup></span> Notably, several recent works revealed that, besides the molecular patterns, specific small molecules can also act as agonists that elicit innate immune responses efficiently.<span><sup>4</sup></span> Several <i>β-</i><span>d</span>-<i>manno</i>-heptose metabolites involved in the biosynthesis of LPSs have been identified as small molecule agonists that can be recognized by host alpha-protein kinase 1 (ALPK1), with ADP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (ADP-heptose) and its C-6′′ epimer as the most potent ones.<span><sup>5</sup></span> Upon binding to ADP-heptose, ALPK1 will undergo conformational changes to phosphorylate TRAF-interacting protein with forkhead-associated domain (TIFA), and then triggers the activation of Nuclear factor kappa B (NF-κB) and inflammation.</p><p>ADP-heptose is synthesized from <span>d</span>-sedoheptulose 7-phosphate (S7P) via a four-step relay catalyzed by NDP-<span>h</span>eptose <span>b</span>iosynthetic <span>e</span>nzymes (HBEs) with isomerase, kinase, phosphatase, and nucleotidyltransferase activities (Figure 1). Three types of <span>H</span>B<span>E</span>s with <span>n</span>ucleotidyltransfer<span>ase</span> (HENase) activities were identified, including monodomain nucleotidyltransferase, didomain kinase/nucleotidyltransferase, and tridomain isomerase/kinase/nucleotidyltransferase.<span><sup>6</sup></span> Before our work, knowledge of HBEs is limited to bacteria. We expanded the understanding of HBEs repertoire beyond the territory of bacteria to viruses, archaea, and eukaryotes.<span><sup>7</sup></span> Enzymatic characterization of HBEs from different kingdoms verified that all of them could synthesize ADP-heptose and some HENases could also recognize CTP and UTP to generate two new heptose metabolites, CDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (CDP-heptose) and UDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (UDP-heptose). Systematic evaluation of the NTP substrate scopes of HENases identified a conserved (F/L)XXG<b>R</b>STT motif (STT<sub>R5</sub>) as a hallmark of HENases with high NTP substrate promiscuity (Figure 1). The fifth arginine residue of the STT<sub>R5</sub> motif may stabilize NTP in a reactive conformation by contributing cation-π interaction with its nucleotide base and hydrogen bonds with its phosphate groups, thereby enabling the HENases to take different NTPs t","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Sauer, Jan Kueckelhaus, Nadja I. Lorenz, Süleyman Bozkurt, Dorothea Schulte, Jan-Béla Weinem, Mohaned Benzarti, Johannes Meiser, Hans Urban, Giulia Villa, Patrick N. Harter, Christian Münch, Johannes Rieger, Joachim P. Steinbach, Dieter Henrik Heiland, Michael W. Ronellenfitsch
Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose.
We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections.
A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment.
Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.
Key Points/Highlights
AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity.
PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma.
PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.
{"title":"An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma","authors":"Benedikt Sauer, Jan Kueckelhaus, Nadja I. Lorenz, Süleyman Bozkurt, Dorothea Schulte, Jan-Béla Weinem, Mohaned Benzarti, Johannes Meiser, Hans Urban, Giulia Villa, Patrick N. Harter, Christian Münch, Johannes Rieger, Joachim P. Steinbach, Dieter Henrik Heiland, Michael W. Ronellenfitsch","doi":"10.1002/ctm2.70030","DOIUrl":"10.1002/ctm2.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose.</p>\u0000 \u0000 <p>We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections.</p>\u0000 \u0000 <p>A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment.</p>\u0000 \u0000 <p>Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Points/Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity.</li>\u0000 \u0000 <li>PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma.</li>\u0000 \u0000 <li>PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Dear Editor,</p><p>Circulating cell-free microRNAs (miRNAs) were rarely explored as biomarkers for early detection of breast cancer (BC) within a screening setting or in prospectively sampled cohorts.<span><sup>1</sup></span> In this study, we confirmed the discriminatory ability of a combination of novel and reliable circulating miRNA-ratio biomarkers, with and without nonmolecular predictors, that could be used for BC early detection in the context of mammographic screening using a standard, affordable, noninvasive and reproducible technique such as quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). The models were built on a discovery case-control set (<i>n</i> = 131) nested within a large mammographic screening cohort,<span><sup>2</sup></span> where more than 14 000 out of 26 640 enrolled women filled an extensive questionnaire on lifestyle habits, hormonal and reproductive history and familiarity for BC, underwent anthropometric measurements and blood sampling. A model with candidate predictors was obtained through penalised logistic regression, and the selected variables were seven plasma miRNA-ratios, breast density, lifestyle score, menopausal status (MS), body mass index (BMI) and their interaction (BMI × MS). Area under the receiver operating characteristic curve (ROC AUC) of .79 for the complete model and of .73 for the miRNA-only model were obtained.<span><sup>3</sup></span> Here, we applied the two models to a new set of women (validation set, <i>n</i> = 159) nested within the same cohort, including cases diagnosed up to four years after blood collection. Table 1 shows the main characteristics of the sample, with a similar distribution of factors between cases and controls except for the number of previous breast biopsies, breastfeeding and waist circumference. The flowchart of the validation study is visualised in Figure 1 and the methods are detailed in the Supplementary Information. Investigating associations between sample characteristics and studied miRNAs, we found weak correlations between BMI and three miRNA-ratios and between WCRF lifestyle score and one miRNA-ratio (Figure S1).</p><p>The cancer characteristics in the discovery and validation sets were similar. However, in the discovery set the diagnosis occurred earlier relative to blood sampling (average 3 months vs. average 25 months), and the proportion of ki-67 positive tumours was lower (23 .5% vs. 82%) (Table S1). Moreover, unlike the discovery set, the validation set included 31 controls that underwent second-level investigation after a suspicious mammogram but then had a negative biopsy. The variables selected in the discovery model were comparable between the two control subgroups (Table S2). Two miRNA-ratios (miR-199a-3p/let-7a-5p and miR-26b-5p/miR-142-5p) were associated with ER status, with <i>p</i>-values of .049 and .027, respectively. Additionally, miR-93-5p/miR-19b-3p was associated with PgR status (<i>p</i> = .036) and let-7b-5p/miR
{"title":"Confirmation of previously identified plasma microRNA ratios for breast cancer detection in a nested case-control study within a screening setting","authors":"Emir Sehovic, Ilaria Gregnanin, Maurizia Mello-Grand, Paola Ostano, Viviana Vergini, Andrea Ortale, Angela Amoruso, Elisabetta Favettini, Nereo Segnan, Giovanna Chiorino, Livia Giordano, Elisabetta Petracci","doi":"10.1002/ctm2.70068","DOIUrl":"10.1002/ctm2.70068","url":null,"abstract":"<p>Dear Editor,</p><p>Circulating cell-free microRNAs (miRNAs) were rarely explored as biomarkers for early detection of breast cancer (BC) within a screening setting or in prospectively sampled cohorts.<span><sup>1</sup></span> In this study, we confirmed the discriminatory ability of a combination of novel and reliable circulating miRNA-ratio biomarkers, with and without nonmolecular predictors, that could be used for BC early detection in the context of mammographic screening using a standard, affordable, noninvasive and reproducible technique such as quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). The models were built on a discovery case-control set (<i>n</i> = 131) nested within a large mammographic screening cohort,<span><sup>2</sup></span> where more than 14 000 out of 26 640 enrolled women filled an extensive questionnaire on lifestyle habits, hormonal and reproductive history and familiarity for BC, underwent anthropometric measurements and blood sampling. A model with candidate predictors was obtained through penalised logistic regression, and the selected variables were seven plasma miRNA-ratios, breast density, lifestyle score, menopausal status (MS), body mass index (BMI) and their interaction (BMI × MS). Area under the receiver operating characteristic curve (ROC AUC) of .79 for the complete model and of .73 for the miRNA-only model were obtained.<span><sup>3</sup></span> Here, we applied the two models to a new set of women (validation set, <i>n</i> = 159) nested within the same cohort, including cases diagnosed up to four years after blood collection. Table 1 shows the main characteristics of the sample, with a similar distribution of factors between cases and controls except for the number of previous breast biopsies, breastfeeding and waist circumference. The flowchart of the validation study is visualised in Figure 1 and the methods are detailed in the Supplementary Information. Investigating associations between sample characteristics and studied miRNAs, we found weak correlations between BMI and three miRNA-ratios and between WCRF lifestyle score and one miRNA-ratio (Figure S1).</p><p>The cancer characteristics in the discovery and validation sets were similar. However, in the discovery set the diagnosis occurred earlier relative to blood sampling (average 3 months vs. average 25 months), and the proportion of ki-67 positive tumours was lower (23 .5% vs. 82%) (Table S1). Moreover, unlike the discovery set, the validation set included 31 controls that underwent second-level investigation after a suspicious mammogram but then had a negative biopsy. The variables selected in the discovery model were comparable between the two control subgroups (Table S2). Two miRNA-ratios (miR-199a-3p/let-7a-5p and miR-26b-5p/miR-142-5p) were associated with ER status, with <i>p</i>-values of .049 and .027, respectively. Additionally, miR-93-5p/miR-19b-3p was associated with PgR status (<i>p</i> = .036) and let-7b-5p/miR","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div> <section> <p>Patients with advanced gastric and colorectal cancers have limited treatment options. Since mesothelin is highly expressed in these tumour types, we evaluated the therapeutic benefits of anti-mesothelin hYP218 CAR T cells alone, and in combination with anti-PD1 antibody, pembrolizumab.</p> <p>GEPIA analysis was performed using human gastric (<i>n</i> = 408) and colon cancer tumours (<i>n</i> = 275) in TCGA database, to evaluate mRNA expression of mesothelin, compared to normal tissues. Mesothelin expression in gastric and colorectal cancer cell-lines (<i>n</i> = 5) was analysed using flow cytometry. In vitro efficacy by hYP218 CAR T cells was tested by cytotoxicity and cytokine release assays. In vivo anti-tumour efficacy of hYP218 CAR T cells alone, and in combination with pembrolizumab, was evaluated in NSG mice bearing human gastric (HGC27) and colorectal (SW48) tumour xenografts. Additionally, hYP218 CAR-T cell persistence, activation and exhaustion marker-expression were studied.</p> <p>Mesothelin expression was significantly higher in gastric and colon cancer biopsies compared to normal tissues (<i>p</i> < .005). Mesothelin expression in gastric and colon cancer cell lines ranged from 10 000 to 70 000 molecules per cell. hYP218 CAR T cells demonstrated strong cytotoxic activity at low effector to target ratio, ranging from 0.24 to 1.0. In NSG mouse-models, hYP218 CAR T cells demonstrated anti-tumour efficacy and persisted in the tumour microenvironment in a functional state at day 40 posttreatment with expression of activation markers CD39 and CD69, increased production of IFN-γ and TNF-α and ability to kill tumour cells in vitro when isolated from tumours. There was increased PD1 expression. In combination with pembrolizumab, hYP218 CAR T cells led to slower tumour growth in NSG mice bearing large but not small HGC27 tumours. Anti-tumour efficacy of hYP218 CAR T cells is due to increased accumulation of activated CAR T cells in the tumour and combination with pembrolizumab resulted in improvement in anti-tumour activity of large established tumours.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Mesothelin expression is significantly higher in gastric and colorectal cancers than normal tissues.</li> <li>hYP218 CAR T cells demonstrate strong anti-tumour activity against mesothelin-positive gastric and colorectal carcinomas.</li> <li>Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity.</li> <li>Addition of pembrolizumab in larger tumours en
晚期胃癌和结直肠癌患者的治疗选择有限。由于间皮素在这些肿瘤类型中高度表达，我们评估了抗间皮素 hYP218 CAR T 细胞单独使用以及与抗 PD1 抗体 pembrolizumab 联合使用的治疗效果。利用TCGA数据库中的人类胃癌（n = 408）和结肠癌肿瘤（n = 275）进行GEPIA分析，评估间皮素与正常组织相比的mRNA表达情况。使用流式细胞术分析了胃癌和结直肠癌细胞系（n = 5）中间皮素的表达。通过细胞毒性和细胞因子释放试验检测了 hYP218 CAR T 细胞的体外疗效。在携带人胃（HGC27）和结直肠（SW48）肿瘤异种移植物的 NSG 小鼠中，评估了 hYP218 CAR T 细胞单独或与 pembrolizumab 联用的体内抗肿瘤疗效。此外，还研究了 hYP218 CAR-T 细胞的持久性、活化和衰竭标记表达。与正常组织相比，胃癌和结肠癌活检组织中间皮素的表达明显更高（p
{"title":"Persistence of activated anti-mesothelin hYP218 chimeric antigen receptor T cells in the tumour is associated with efficacy in gastric and colorectal carcinomas","authors":"Sameer Mir, Abhilash Venugopalan, Jingli Zhang, Nishanth Ulhas Nair, Manjistha Sengupta, Manakamana Khanal, Chaido Stathopoulou, Qun Jiang, Raffit Hassan","doi":"10.1002/ctm2.70057","DOIUrl":"10.1002/ctm2.70057","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Patients with advanced gastric and colorectal cancers have limited treatment options. Since mesothelin is highly expressed in these tumour types, we evaluated the therapeutic benefits of anti-mesothelin hYP218 CAR T cells alone, and in combination with anti-PD1 antibody, pembrolizumab.</p>\u0000 \u0000 <p>GEPIA analysis was performed using human gastric (<i>n</i> = 408) and colon cancer tumours (<i>n</i> = 275) in TCGA database, to evaluate mRNA expression of mesothelin, compared to normal tissues. Mesothelin expression in gastric and colorectal cancer cell-lines (<i>n</i> = 5) was analysed using flow cytometry. In vitro efficacy by hYP218 CAR T cells was tested by cytotoxicity and cytokine release assays. In vivo anti-tumour efficacy of hYP218 CAR T cells alone, and in combination with pembrolizumab, was evaluated in NSG mice bearing human gastric (HGC27) and colorectal (SW48) tumour xenografts. Additionally, hYP218 CAR-T cell persistence, activation and exhaustion marker-expression were studied.</p>\u0000 \u0000 <p>Mesothelin expression was significantly higher in gastric and colon cancer biopsies compared to normal tissues (<i>p</i> < .005). Mesothelin expression in gastric and colon cancer cell lines ranged from 10 000 to 70 000 molecules per cell. hYP218 CAR T cells demonstrated strong cytotoxic activity at low effector to target ratio, ranging from 0.24 to 1.0. In NSG mouse-models, hYP218 CAR T cells demonstrated anti-tumour efficacy and persisted in the tumour microenvironment in a functional state at day 40 posttreatment with expression of activation markers CD39 and CD69, increased production of IFN-γ and TNF-α and ability to kill tumour cells in vitro when isolated from tumours. There was increased PD1 expression. In combination with pembrolizumab, hYP218 CAR T cells led to slower tumour growth in NSG mice bearing large but not small HGC27 tumours. Anti-tumour efficacy of hYP218 CAR T cells is due to increased accumulation of activated CAR T cells in the tumour and combination with pembrolizumab resulted in improvement in anti-tumour activity of large established tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Mesothelin expression is significantly higher in gastric and colorectal cancers than normal tissues.</li>\u0000 \u0000 <li>hYP218 CAR T cells demonstrate strong anti-tumour activity against mesothelin-positive gastric and colorectal carcinomas.</li>\u0000 \u0000 <li>Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity.</li>\u0000 \u0000 <li>Addition of pembrolizumab in larger tumours en","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pituitary neuroendocrine tumours (PitNETs) are common intracranial tumours that are highly heterogeneous with unpredictable growth patterns. The driver genes and mechanisms that are crucial for tumour progression in somatotroph PitNETs are poorly understood.
Methods
In this study, we performed integrative spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) analysis on somatotroph tumours and normal pituitary samples to comprehensively characterize the differences in cellular characteristics.
Results
By analyzing combined copy number variations (CNVs), tumour tissues were divided into two regions, which included the CNVhigh and CNVlow areas. The protumour genes DLK1 and RCN1 were highly expressed in the CNVhigh area, which might be related to tumour progression and could be targeted for precision therapy. We also found that the transforming growth factor beta signalling pathway participated in tumour progression and identified heterogeneity in the expression profiles of key genes. We assessed the intertumoral and intratumoral heterogeneity in somatotroph PitNETs and emphasized the importance of individualized treatment.
Conclusion
In summary, we visualized the cellular distribution and transcriptional differences in normal pituitary and somatotroph PitNETs by ST and scRNA-seq for the first time. This study provides a strong theoretical foundation to comprehensively understand the crucial mechanisms involved in tumour progression and develop new strategies to treat somatotroph PitNETs.
Key points
The first-ever visualization of cellular distributions in normal and tumor pituitary tissues.
The inter- and intra-tumoral transcriptomic heterogeneity of somatotroph PitNETs was comprehensively revealed.
Identification of potential protumor factors and critical signaling pathways, opening new avenues for therapeutic intervention.
背景：垂体神经内分泌肿瘤（PitNETs）是一种常见的颅内肿瘤，具有高度异质性和不可预测的生长模式。人们对嗜体细胞性垂体神经内分泌肿瘤（PitNETs）肿瘤进展的驱动基因和机制知之甚少：在这项研究中，我们对嗜体细胞肿瘤和正常垂体样本进行了空间转录组学（ST）和单细胞RNA测序（scRNA-seq）综合分析，以全面描述细胞特征的差异：通过分析合并拷贝数变异（CNV），肿瘤组织被分为两个区域，包括CNV高区和CNV低区。原肿瘤基因DLK1和RCN1在CNV高区高表达，这可能与肿瘤进展有关，可作为精准治疗的靶点。我们还发现转化生长因子β信号通路参与了肿瘤的进展，并确定了关键基因表达谱的异质性。我们评估了瘤间和瘤内的异质性，强调了个体化治疗的重要性：总之，我们通过 ST 和 scRNA-seq 技术首次直观地了解了正常垂体和嗜体细胞 PitNET 的细胞分布和转录差异。这项研究为全面了解肿瘤进展的关键机制和开发治疗体细胞嗜养型PitNETs的新策略提供了坚实的理论基础：首次观察到正常和肿瘤垂体组织中的细胞分布。全面揭示了瘤间和瘤内的转录组异质性。确定了潜在的原发肿瘤因子和关键信号通路，为治疗干预开辟了新途径。
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