Targeted delivery of anti-tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.
{"title":"Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance","authors":"Chen Ming-Kun, Chen Zi-Xian, Cai Mao-Ping, Chen Hong, Chen Zhuang-Fei, Zhao Shan-Chao","doi":"10.1002/cac2.12518","DOIUrl":"10.1002/cac2.12518","url":null,"abstract":"<p>Targeted delivery of anti-tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 2","pages":"205-225"},"PeriodicalIF":16.2,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139058139","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>Brain metastasis (BM) has long been recognized as a prognostic factor associated with poor prognosis for non-small cell lung cancer (NSCLC) in the era of conventional chemotherapy and targeted therapy [<span>1</span>]. In the era of immunotherapy, controversial findings have been reported regarding the prognostic significance of BM in patients with NSCLC treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Several studies have shown that the presence of BM did not impact overall survival (OS) or progression-free survival (PFS) [<span>2, 3</span>], whereas other studies have identified BM as a negative prognostic factor [<span>4, 5</span>]. These previous works were mostly based on small sample sizes, and the prognostic significance of BM in patients treated with PD-1/PD-L1 inhibitors warrants further investigation.</p><p>In the present study, we used Vivli, a global, neutral data-sharing platform that enables access to anonymized individual patient data from trials, to evaluate the association between previously irradiated stable BM (iBM) and treatment outcomes of atezolizumab-containing regimens using pooled data from prospective phase III trials. Three clinical trials, IMpower130 (NCT02367781) [<span>6</span>], IMpower131 (NCT02367794) [<span>7</span>], and IMpower150 (NCT02366143) [<span>8</span>], were identified. Supplementary Table S1 provides an overview of the included three clinical trials. The study design and methods are described in the Supplementary Material.</p><p>Supplementary Figure S1 shows the patient disposition for the per-protocol population. In the per-protocol population (<i>n</i> = 2,700), only 10 (3.3%) of 316 patients with baseline BM did not undergo previous irradiation, who were excluded due to difficulties in statistical analyses. Among the 2,690 patients finally included, 210 (11.8%) of 1,778 patients in the atezolizumab-containing arm and 96 (10.5%) of 912 patients in the chemotherapy alone arm had iBM. Baseline demographics and clinical characteristics for patients without baseline BM and patients with iBM are shown in Supplementary Table S2. In patients without BM, OS and PFS were improved with atezolizumab-containing regimens compared with chemotherapy alone (Supplementary Figure S2). In patients with iBM, adding atezolizumab significantly improved OS and PFS compared with chemotherapy alone (Supplementary Figure S3).</p><p>We utilized propensity score matching (PSM) to control for the heterogeneity between patients with iBM and those without BM (Supplementary Table S3). A total of 11 patients in the atezolizumab-containing arm and 10 in the chemotherapy alone arm were excluded due to missing relevant baseline characteristic data. We compared the OS of patients with iBM and those without baseline BM before and after PSM (Figure 1). In the atezolizumab-containing arm, OS was longer in patients with iBM than in those without BM in the original cohort (unadjusted hazard ratio [HR] =
在传统化疗和靶向治疗时代，脑转移（BM）一直被认为是与非小细胞肺癌（NSCLC）不良预后相关的预后因素[1]。在免疫疗法时代，关于程序性死亡-1/程序性死亡配体 1（PD-1/PD-L1）抑制剂治疗的 NSCLC 患者 BM 的预后意义，已有争议性的研究结果。一些研究表明，BM 的存在并不影响总生存期（OS）或无进展生存期（PFS）[2, 3]，而另一些研究则认为 BM 是一个负面的预后因素[4, 5]。在本研究中，我们使用 Vivli（一个全球性、中立的数据共享平台，可访问试验中匿名的患者个体数据），利用前瞻性 III 期试验的汇总数据评估了既往照射过的稳定 BM（iBM）与含阿特珠单抗方案治疗结果之间的关联。共确定了三项临床试验：IMpower130（NCT02367781）[6]、IMpower131（NCT02367794）[7]和IMpower150（NCT02366143）[8]。补充表 S1 提供了所纳入的三项临床试验的概况。研究设计和方法见补充材料。补充图 S1 显示了按协议人群的患者处置情况。在按协议人群（n = 2,700）中，基线BM的316名患者中仅有10人（3.3%）既往未接受过照射，由于统计分析困难而被排除在外。在最终纳入的 2,690 名患者中，含阿替珠单抗治疗组的 1,778 名患者中有 210 人（11.8%）患有 iBM，而单纯化疗组的 912 名患者中有 96 人（10.5%）患有 iBM。无基线BM患者和有iBM患者的基线人口统计学特征和临床特征见补充表S2。与单纯化疗相比，在无基础骨髓瘤的患者中，使用含有阿特珠单抗的方案可改善OS和PFS（补充图S2）。在iBM患者中，与单纯化疗相比，添加atezolizumab能显著改善OS和PFS（补充图S3）。我们利用倾向评分匹配（PSM）来控制iBM患者与无BM患者之间的异质性（补充表S3）。由于缺失相关基线特征数据，共排除了含阿替珠单抗治疗组的11例患者和单纯化疗组的10例患者。我们比较了iBM患者和无基线BM患者在PSM前后的OS（图1）。在含有阿特珠单抗的治疗组中，原始队列中的iBM患者的OS长于无BM患者（未经调整的危险比[HR] = 0.75，95%置信区间[CI] = 0.60-0.93，P = 0.011；调整后的HR = 0.75，95% CI = 0.60-0.95，P = 0.015；补充表S4），倾向评分匹配队列中的iBM患者的OS也长于无BM患者（未经调整的HR = 0.35, 95% CI = 0.27-0.45, P < 0.001; 调整后 HR = 0.26, 95% CI = 0.20-0.33, P < 0.001; 补充表 S5）；在单纯化疗组中，原始队列和倾向评分匹配队列中的 iBM 患者与无 BM 患者的 OS 相似。在 PSM 前后，治疗组与 BM 状态之间存在明显的交互作用（Pinteraction = 0.013，Pinteraction < 0.001）。我们还应用了稳定的反概率加权法，得到了相似的结果（补充表 S6 和补充图 S4）。我们还比较了有 iBM 和无基线 BM 患者的 PFS，结果见补充图 S5-S6 和补充表 S7-S10。此外，我们还比较了无BM患者和有放疗技术信息的iBM患者的OS和PFS，发现放射外科治疗的稳定BM或全脑放疗治疗的稳定BM与PSM后含阿特珠单抗组生存率的改善有关，但与单纯化疗组无关（补充图S7-S10）。225例（14.3%）无基线BM的患者和31例（14.8%）iBM患者发生了任何级别的阿特珠单抗相关神经系统不良事件（AEs）；19例（1.2%）无基线BM的患者和4例（1.9%）iBM患者发生了阿特珠单抗相关的3/4级神经系统不良事件（补充表S11）。无BM患者和iBM患者发生atezolizumab相关严重神经系统AEs的比例相似（0.7% vs. 0.4%）。最常见的atezolizumab相关神经系统AE是无基线BM患者的头痛和iBM患者的周围神经病变（补充表S12）。
{"title":"Association of previously irradiated stable brain metastases with outcomes of atezolizumab-treated non-small cell lung cancer: A pooled analysis of individual patient data from three randomized trials","authors":"Tiantian Guo, Yue Zhou, Fei Liang, Zezhou Wang, Vincent Bourbonne, Lukas Käsmann, Nora Sundahl, Abraham Jing-Ching Wu, Jianjiao Ni, Zhengfei Zhu","doi":"10.1002/cac2.12512","DOIUrl":"10.1002/cac2.12512","url":null,"abstract":"<p>Brain metastasis (BM) has long been recognized as a prognostic factor associated with poor prognosis for non-small cell lung cancer (NSCLC) in the era of conventional chemotherapy and targeted therapy [<span>1</span>]. In the era of immunotherapy, controversial findings have been reported regarding the prognostic significance of BM in patients with NSCLC treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Several studies have shown that the presence of BM did not impact overall survival (OS) or progression-free survival (PFS) [<span>2, 3</span>], whereas other studies have identified BM as a negative prognostic factor [<span>4, 5</span>]. These previous works were mostly based on small sample sizes, and the prognostic significance of BM in patients treated with PD-1/PD-L1 inhibitors warrants further investigation.</p><p>In the present study, we used Vivli, a global, neutral data-sharing platform that enables access to anonymized individual patient data from trials, to evaluate the association between previously irradiated stable BM (iBM) and treatment outcomes of atezolizumab-containing regimens using pooled data from prospective phase III trials. Three clinical trials, IMpower130 (NCT02367781) [<span>6</span>], IMpower131 (NCT02367794) [<span>7</span>], and IMpower150 (NCT02366143) [<span>8</span>], were identified. Supplementary Table S1 provides an overview of the included three clinical trials. The study design and methods are described in the Supplementary Material.</p><p>Supplementary Figure S1 shows the patient disposition for the per-protocol population. In the per-protocol population (<i>n</i> = 2,700), only 10 (3.3%) of 316 patients with baseline BM did not undergo previous irradiation, who were excluded due to difficulties in statistical analyses. Among the 2,690 patients finally included, 210 (11.8%) of 1,778 patients in the atezolizumab-containing arm and 96 (10.5%) of 912 patients in the chemotherapy alone arm had iBM. Baseline demographics and clinical characteristics for patients without baseline BM and patients with iBM are shown in Supplementary Table S2. In patients without BM, OS and PFS were improved with atezolizumab-containing regimens compared with chemotherapy alone (Supplementary Figure S2). In patients with iBM, adding atezolizumab significantly improved OS and PFS compared with chemotherapy alone (Supplementary Figure S3).</p><p>We utilized propensity score matching (PSM) to control for the heterogeneity between patients with iBM and those without BM (Supplementary Table S3). A total of 11 patients in the atezolizumab-containing arm and 10 in the chemotherapy alone arm were excluded due to missing relevant baseline characteristic data. We compared the OS of patients with iBM and those without baseline BM before and after PSM (Figure 1). In the atezolizumab-containing arm, OS was longer in patients with iBM than in those without BM in the original cohort (unadjusted hazard ratio [HR] = ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 2","pages":"278-281"},"PeriodicalIF":16.2,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12512","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139037363","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}
Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.
Methods
We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.
Results
Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT-rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling.
Conclusion
Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.
{"title":"Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma","authors":"Weiren Liu, Huqiang Wang, Qianfu Zhao, Chenyang Tao, Weifeng Qu, Yushan Hou, Run Huang, Zimei Sun, Guiqi Zhu, Xifei Jiang, Yuan Fang, Jun Gao, Xiaoling Wu, Zhixiang Yang, Rongyu Ping, Jiafeng Chen, Rui Yang, Tianhao Chu, Jian Zhou, Jia Fan, Zheng Tang, Dong Yang, Yinghong Shi","doi":"10.1002/cac2.12513","DOIUrl":"10.1002/cac2.12513","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>)/AT-rich interactive domain 1A (<i>ARID1A</i>) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 2","pages":"226-250"},"PeriodicalIF":16.2,"publicationDate":"2023-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032184","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}
Monika Raab, Izabela Kostova, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Seyed Mohsen Aberoumandi, Evelyn Ullrich, Sven Becker, Mourad Sanhaji, Klaus Strebhardt
<div> <section> <h3> Background</h3> <p>The cellular tumor protein p53 (<i>TP53</i>) is a tumor suppressor gene that is frequently mutated in human cancers. Among various cancer types, the very aggressive high-grade serous ovarian carcinoma (HGSOC) exhibits the highest prevalence of <i>TP53</i> mutations, present in >96% of cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved to rescue p53 function. In this study, our primary objective was to administer in vitro-transcribed (IVT) wild-type (WT) p53-mRNA to HGSOC cell lines, primary cells, and orthotopic mouse models, with the aim of exploring its impact on inhibiting tumor growth and dissemination, both in vitro and in vivo.</p> </section> <section> <h3> Methods</h3> <p>To restore the activity of p53, WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system. Moreover, IVT WT p53 mRNA was delivered into different HGSOC model systems (primary cells and patient-derived organoids) using liposomes and studied for proliferation, cell cycle progression, apoptosis, colony formation, and chromosomal instability. Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells, followed by ingenuity pathway analysis. In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.</p> </section> <section> <h3> Results</h3> <p>Reactivation of the <i>TP53</i> tumor suppressor gene was explored in different HGSOC model systems using newly designed IVT mRNA-based methods. The introduction of WT p53 mRNA triggered dose-dependent apoptosis, cell cycle arrest, and potent long-lasting inhibition of HGSOC cell proliferation. Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling, such as apoptosis, cell cycle regulation, and DNA damage. Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells, underscoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress. Furthermore, in various mouse models, treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.</p> </section> <section> <h3> Conclusions</h3> <p>The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC, providing valuable insights into
{"title":"Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer","authors":"Monika Raab, Izabela Kostova, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Seyed Mohsen Aberoumandi, Evelyn Ullrich, Sven Becker, Mourad Sanhaji, Klaus Strebhardt","doi":"10.1002/cac2.12511","DOIUrl":"10.1002/cac2.12511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The cellular tumor protein p53 (<i>TP53</i>) is a tumor suppressor gene that is frequently mutated in human cancers. Among various cancer types, the very aggressive high-grade serous ovarian carcinoma (HGSOC) exhibits the highest prevalence of <i>TP53</i> mutations, present in >96% of cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved to rescue p53 function. In this study, our primary objective was to administer in vitro-transcribed (IVT) wild-type (WT) p53-mRNA to HGSOC cell lines, primary cells, and orthotopic mouse models, with the aim of exploring its impact on inhibiting tumor growth and dissemination, both in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To restore the activity of p53, WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system. Moreover, IVT WT p53 mRNA was delivered into different HGSOC model systems (primary cells and patient-derived organoids) using liposomes and studied for proliferation, cell cycle progression, apoptosis, colony formation, and chromosomal instability. Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells, followed by ingenuity pathway analysis. In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Reactivation of the <i>TP53</i> tumor suppressor gene was explored in different HGSOC model systems using newly designed IVT mRNA-based methods. The introduction of WT p53 mRNA triggered dose-dependent apoptosis, cell cycle arrest, and potent long-lasting inhibition of HGSOC cell proliferation. Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling, such as apoptosis, cell cycle regulation, and DNA damage. Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells, underscoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress. Furthermore, in various mouse models, treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC, providing valuable insights into ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 1","pages":"101-126"},"PeriodicalIF":16.2,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138884486","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}
Ji Eon Kim, So-Young Park, Chulhwan Kwak, Yoonji Lee, Dae-Geun Song, Jae Woo Jung, Haesong Lee, Eun-Ae Shin, Yangie Pinanga, Kyung-hee Pyo, Eun Hae Lee, Wonsik Kim, Soyeon Kim, Chang-Duck Jun, Jeanho Yun, Sun Choi, Hyun-Woo Rhee, Kwang-Hyeon Liu, Jung Weon Lee
Background
Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.
Methods
Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc.
Results
Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.
Conclusions
Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.
{"title":"Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites","authors":"Ji Eon Kim, So-Young Park, Chulhwan Kwak, Yoonji Lee, Dae-Geun Song, Jae Woo Jung, Haesong Lee, Eun-Ae Shin, Yangie Pinanga, Kyung-hee Pyo, Eun Hae Lee, Wonsik Kim, Soyeon Kim, Chang-Duck Jun, Jeanho Yun, Sun Choi, Hyun-Woo Rhee, Kwang-Hyeon Liu, Jung Weon Lee","doi":"10.1002/cac2.12510","DOIUrl":"10.1002/cac2.12510","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 1","pages":"47-75"},"PeriodicalIF":16.2,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138828322","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}
Bianca Cesaro, Alessia Iaiza, Fabio Piscopo, Marco Tarullo, Eleonora Cesari, Dante Rotili, Antonello Mai, Alberto Diana, Michela Londero, Luca Del Giacco, Riccardo Masetti, Alba Di Leone, Chiara Naro, Silvia Masciarelli, Giulia Fontemaggi, Claudio Sette, Francesco Fazi, Alessandro Fatica
<p>Dear Editor,</p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is a critical mRNA modification catalyzed by the enzyme methyltransferase-like 3 (METTL3), with implications in RNA metabolism. METTL3 upregulation is associated with cancer progression, metastasis, and drug resistance, making it a potential therapeutic target [<span>1</span>]. The small-molecule METTL3 inhibitor, STM2457, has shown promise in treating acute myeloid leukemia (AML) and has demonstrated good tolerance in mice [<span>2, 3</span>]. However, the specific cancer types where METTL3 inhibitors are most effective remain unknown.</p><p>In breast cancer, <i>METTL3</i> knockdown markedly suppresses proliferation, invasiveness, and metastasis [<span>4</span>]. Therefore, METTL3 inhibition is proposed as a therapeutic approach for breast cancer. Triple-negative breast cancer (TNBC), the most aggressive subtype, lacks targeted therapies, and its primary treatments involve conventional chemotherapy and DNA-damaging agents [<span>5</span>]. Homologous recombination deficiency, such as mutations in the breast cancer gene 1 (<i>BRCA1</i>) and <i>BRCA2</i>, serves as a predictive biomarker for identifying patients who would benefit from genotoxic chemotherapy and poly(ADP-ribose) polymerase (<i>PARP</i>) inhibitors. Notably, METTL3 is recruited to DNA-damaged sites and is crucial for subsequent DNA repair [<span>6, 7</span>]. Consequently, <i>METTL3</i> knockdown reduces DNA repair activity and sensitizes cancer cells to genotoxic drugs [<span>7, 8</span>]. However, while TNBC exhibits elevated METTL3 levels, and its nuclear catalytic activity associates with invasiveness and metastasis [<span>9</span>], it remains uncertain whether METTL3 inhibition enhances chemotherapy response in TNBC.</p><p>Here, we aimed to explore the potential of METTL3 catalytic inhibition by STM2457 as a valuable treatment option for TNBC. Furthermore, we assessed the impact of STM2457 on the sensitivity of TNBC cells and a TNBC patient-derived organoid line to clinical DNA-damaging therapies, like platinum-based chemotherapy and the PARP inhibitor olaparib (Supplementary file of methods).</p><p>STM2457 significantly reduced the proliferation and viability of TNBC cells, including both <i>BRCA1/2</i> wild-type (MDA-MB-231 and MDA-MB-468) and <i>BRCA1</i>-mutated (MDA-MB-436, HCC1395, and HCC1937) cell lines. STM2457 exhibited negligible effects on the proliferation of non-tumoral breast epithelial cells (MCF-10A), with significant reduction observed only at the highest concentration tested (100 μmol/L) (Figure 1A, Supplementary Figure S1A-B). The treatment with 10 μmol/L STM2457 for 48 h decreased the global m<sup>6</sup>A levels in mRNA by approximately 50% in both MDA-MB-231 and MCF-10A cells (Supplementary Figure S1C). Colony formation assays further confirmed the anti-proliferative impact of STM2457 on TNBC cell lines (Figure 1B, Supplementary Figure S2). Moreover, wound healing assays indicated that
{"title":"Enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase METTL3","authors":"Bianca Cesaro, Alessia Iaiza, Fabio Piscopo, Marco Tarullo, Eleonora Cesari, Dante Rotili, Antonello Mai, Alberto Diana, Michela Londero, Luca Del Giacco, Riccardo Masetti, Alba Di Leone, Chiara Naro, Silvia Masciarelli, Giulia Fontemaggi, Claudio Sette, Francesco Fazi, Alessandro Fatica","doi":"10.1002/cac2.12509","DOIUrl":"10.1002/cac2.12509","url":null,"abstract":"<p>Dear Editor,</p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is a critical mRNA modification catalyzed by the enzyme methyltransferase-like 3 (METTL3), with implications in RNA metabolism. METTL3 upregulation is associated with cancer progression, metastasis, and drug resistance, making it a potential therapeutic target [<span>1</span>]. The small-molecule METTL3 inhibitor, STM2457, has shown promise in treating acute myeloid leukemia (AML) and has demonstrated good tolerance in mice [<span>2, 3</span>]. However, the specific cancer types where METTL3 inhibitors are most effective remain unknown.</p><p>In breast cancer, <i>METTL3</i> knockdown markedly suppresses proliferation, invasiveness, and metastasis [<span>4</span>]. Therefore, METTL3 inhibition is proposed as a therapeutic approach for breast cancer. Triple-negative breast cancer (TNBC), the most aggressive subtype, lacks targeted therapies, and its primary treatments involve conventional chemotherapy and DNA-damaging agents [<span>5</span>]. Homologous recombination deficiency, such as mutations in the breast cancer gene 1 (<i>BRCA1</i>) and <i>BRCA2</i>, serves as a predictive biomarker for identifying patients who would benefit from genotoxic chemotherapy and poly(ADP-ribose) polymerase (<i>PARP</i>) inhibitors. Notably, METTL3 is recruited to DNA-damaged sites and is crucial for subsequent DNA repair [<span>6, 7</span>]. Consequently, <i>METTL3</i> knockdown reduces DNA repair activity and sensitizes cancer cells to genotoxic drugs [<span>7, 8</span>]. However, while TNBC exhibits elevated METTL3 levels, and its nuclear catalytic activity associates with invasiveness and metastasis [<span>9</span>], it remains uncertain whether METTL3 inhibition enhances chemotherapy response in TNBC.</p><p>Here, we aimed to explore the potential of METTL3 catalytic inhibition by STM2457 as a valuable treatment option for TNBC. Furthermore, we assessed the impact of STM2457 on the sensitivity of TNBC cells and a TNBC patient-derived organoid line to clinical DNA-damaging therapies, like platinum-based chemotherapy and the PARP inhibitor olaparib (Supplementary file of methods).</p><p>STM2457 significantly reduced the proliferation and viability of TNBC cells, including both <i>BRCA1/2</i> wild-type (MDA-MB-231 and MDA-MB-468) and <i>BRCA1</i>-mutated (MDA-MB-436, HCC1395, and HCC1937) cell lines. STM2457 exhibited negligible effects on the proliferation of non-tumoral breast epithelial cells (MCF-10A), with significant reduction observed only at the highest concentration tested (100 μmol/L) (Figure 1A, Supplementary Figure S1A-B). The treatment with 10 μmol/L STM2457 for 48 h decreased the global m<sup>6</sup>A levels in mRNA by approximately 50% in both MDA-MB-231 and MCF-10A cells (Supplementary Figure S1C). Colony formation assays further confirmed the anti-proliferative impact of STM2457 on TNBC cell lines (Figure 1B, Supplementary Figure S2). Moreover, wound healing assays indicated that ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 2","pages":"282-286"},"PeriodicalIF":16.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138741751","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}
Yuting Li, Hanhao Zheng, Yuming Luo, Yan Lin, Mingjie An, Yao Kong, Yue Zhao, Yina Yin, Le Ai, Jian Huang, Changhao Chen
The cover image is based on the Original Article An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis by Yuting Li et al., https://doi.org/10.1002/cac2.12470.
{"title":"Cover Image, Volume 43, Issue 12","authors":"Yuting Li, Hanhao Zheng, Yuming Luo, Yan Lin, Mingjie An, Yao Kong, Yue Zhao, Yina Yin, Le Ai, Jian Huang, Changhao Chen","doi":"10.1002/cac2.12508","DOIUrl":"https://doi.org/10.1002/cac2.12508","url":null,"abstract":"<p>The cover image is based on the Original Article <i>An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis</i> by Yuting Li et al., https://doi.org/10.1002/cac2.12470.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"43 12","pages":"i"},"PeriodicalIF":16.2,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138475622","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}
Chenchen Liu, Aiwen Shen, Junquan Song, Lei Cheng, Meng Zhang, Yanong Wang, Xiaowen Liu
<div> <section> <h3> Background</h3> <p>Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis.</p> </section> <section> <h3> Methods</h3> <p>LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD.</p> </section> <section> <h3> Results</h3> <p>We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3<sup>Y705</sup> dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnt<sup>high</sup> GC, but not Wnt<sup>low</sup> GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnt<sup>high</sup> PDX mice.</p> </section> <section> <h3> Conclusions</h3> <p>We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study r
{"title":"LncRNA-CCAT5-mediated crosstalk between Wnt/β-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity","authors":"Chenchen Liu, Aiwen Shen, Junquan Song, Lei Cheng, Meng Zhang, Yanong Wang, Xiaowen Liu","doi":"10.1002/cac2.12507","DOIUrl":"10.1002/cac2.12507","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3<sup>Y705</sup> dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnt<sup>high</sup> GC, but not Wnt<sup>low</sup> GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnt<sup>high</sup> PDX mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study r","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 1","pages":"76-100"},"PeriodicalIF":16.2,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443897","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}
Jin Wang, Ming-Jia Xi, Qing Lu, Bi-Han Xia, Yu-Zhi Liu, Jin-Lin Yang
<p>Dear Editor,</p><p>Cancer-associated fibroblasts (CAFs) are highly versatile and plastic cells in the tumor microenvironment. They have been identified as actively involved in cancer progression and metastasis through their various roles in remodeling the extracellular matrix, suppressing the immune response and reprogramming tumor metabolism [<span>1</span>]. However, many challenges exist in revealing the functional phenotypes and mechanisms of CAFs in different cancers due to limited understanding of CAF heterogeneity [<span>2</span>]. Recent advances in single-cell transcriptome technology have enabled the identification of distinct CAF subpopulations by using unique gene signatures in multiple tumor types [<span>2</span>]. In this study, we successfully identified a tumor-specific CD36<sup>+</sup> CAF subpopulation in colorectal cancer (CRC), which was found to be correlated with the number of tumor-infiltrated immune cells.</p><p>Primary CAFs and normal fibroblasts (NFs) were isolated from 5 fresh CRC tissues and paired normal colon tissues. Isolation methods and descriptions of other assays are shown in the Supplementary Methods. Immunofluorescence and Western blotting assays showed that the mesenchymal marker Vimentin was expressed in both NFs and CAFs, while alpha smooth muscle actin (αSMA) and fibroblast-specific protein 1 (FSP1) were overexpressed in CAFs (Supplementary Figure S1A-D). To further investigate gene expression profiles in these fibroblasts, primary NFs and CAFs were subjected to RNA sequencing. The results showed that CD36 was significantly upregulated in CAFs (Supplementary Figure S1E), which was further validated by immunofluorescence and Western blotting assays (Supplementary Figure S1F-G). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differentially expressed genes between NFs and CAFs indicated significant enrichment in the mitogen-activated protein kinase (MAPK) signaling pathway, phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway and receptor-ligand activity (Supplementary Figure S1H-I), suggesting that CAFs may play a critical role in intracellular and extracellular signal transduction.</p><p>Previous studies have demonstrated that CAFs achieve high heterogeneity and plasticity across different cancer types [<span>1, 2</span>]. To further reveal the characteristics of CAFs in CRC, we performed single-cell RNA-sequencing (scRNA-seq) using isolated NFs and CAFs and detected 21,248 NFs and 18,097 CAFs (Figure 1A). A total of 7 clusters were identified in these fibroblasts by using sample integration analysis based on distinct gene expression signatures. Interestingly, we found that Clusters 3, 5, and 7 were mainly distributed in the CAF group, accounting for 34.5%, 7.7%, and 2.3% of total CAFs, respectively (Figure 1B-E). Cluster gene signature analysis showed that CD36 was expressed in CAF-specific subgroups, such as Clusters 3 and 5; inhibin subunit beta A (INHBA) was m
{"title":"Single-cell and bulk transcriptomics identifies a tumor-specific CD36+ cancer-associated fibroblast subpopulation in colorectal cancer","authors":"Jin Wang, Ming-Jia Xi, Qing Lu, Bi-Han Xia, Yu-Zhi Liu, Jin-Lin Yang","doi":"10.1002/cac2.12506","DOIUrl":"10.1002/cac2.12506","url":null,"abstract":"<p>Dear Editor,</p><p>Cancer-associated fibroblasts (CAFs) are highly versatile and plastic cells in the tumor microenvironment. They have been identified as actively involved in cancer progression and metastasis through their various roles in remodeling the extracellular matrix, suppressing the immune response and reprogramming tumor metabolism [<span>1</span>]. However, many challenges exist in revealing the functional phenotypes and mechanisms of CAFs in different cancers due to limited understanding of CAF heterogeneity [<span>2</span>]. Recent advances in single-cell transcriptome technology have enabled the identification of distinct CAF subpopulations by using unique gene signatures in multiple tumor types [<span>2</span>]. In this study, we successfully identified a tumor-specific CD36<sup>+</sup> CAF subpopulation in colorectal cancer (CRC), which was found to be correlated with the number of tumor-infiltrated immune cells.</p><p>Primary CAFs and normal fibroblasts (NFs) were isolated from 5 fresh CRC tissues and paired normal colon tissues. Isolation methods and descriptions of other assays are shown in the Supplementary Methods. Immunofluorescence and Western blotting assays showed that the mesenchymal marker Vimentin was expressed in both NFs and CAFs, while alpha smooth muscle actin (αSMA) and fibroblast-specific protein 1 (FSP1) were overexpressed in CAFs (Supplementary Figure S1A-D). To further investigate gene expression profiles in these fibroblasts, primary NFs and CAFs were subjected to RNA sequencing. The results showed that CD36 was significantly upregulated in CAFs (Supplementary Figure S1E), which was further validated by immunofluorescence and Western blotting assays (Supplementary Figure S1F-G). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differentially expressed genes between NFs and CAFs indicated significant enrichment in the mitogen-activated protein kinase (MAPK) signaling pathway, phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway and receptor-ligand activity (Supplementary Figure S1H-I), suggesting that CAFs may play a critical role in intracellular and extracellular signal transduction.</p><p>Previous studies have demonstrated that CAFs achieve high heterogeneity and plasticity across different cancer types [<span>1, 2</span>]. To further reveal the characteristics of CAFs in CRC, we performed single-cell RNA-sequencing (scRNA-seq) using isolated NFs and CAFs and detected 21,248 NFs and 18,097 CAFs (Figure 1A). A total of 7 clusters were identified in these fibroblasts by using sample integration analysis based on distinct gene expression signatures. Interestingly, we found that Clusters 3, 5, and 7 were mainly distributed in the CAF group, accounting for 34.5%, 7.7%, and 2.3% of total CAFs, respectively (Figure 1B-E). Cluster gene signature analysis showed that CD36 was expressed in CAF-specific subgroups, such as Clusters 3 and 5; inhibin subunit beta A (INHBA) was m","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"495-498"},"PeriodicalIF":16.2,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290446","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}
Lucia Chica-Redecillas, Sergio Cuenca-Lopez, Eduardo Andres-Leon, Laura Carmen Terron-Camero, Blanca Cano-Gutierrez, Jose Manuel Cozar, Jose Antonio Lorente, Fernando Vazquez-Alonso, Luis Javier Martinez-Gonzalez, Maria Jesus Alvarez-Cubero
<p>Dear Editor,</p><p>Hereditary prostate cancer (PC) comprises 5%-10% of all PC cases. The increased risk of PC in men with a family history of the disease is well known and is commonly caused by germline mutations, leading to clinical guidelines mentioning various genes for identifying high-risk individuals. However, the complex inheritance patterns involving multiple single nucleotide polymorphisms (SNPs) make it a genetically heterogeneous disease, with genetic testing still in its early stages. Current guidelines, such as those from the National Comprehensive Cancer Network (NCCN), are insufficient to identify and stratify all PC patients [<span>1</span>]. To improve testing and screening for familial PC, we report a multi-omic analysis (Supplementary Figures S1-S2) in a PC multi-case family of seven members (two healthy, four PC, and one breast cancer) (Figure 1A, Supplementary Table S1) combining exome, transcriptome and epigenomic analyses (whole-DNA methylation and small-RNA sequencing), offering a unique perspective on the understanding of hereditary PC to date. Each family is a small genetic unit that differs significantly from others with the same pathology but different genetic origins. Therefore, individualized studies may be the key to unravel the heterogeneity of this disease. However, we need to consider that conducting futuremetabolomic analysis would be next steps to reinforce present data, as well as reproducible analysis in other PC families.</p><p>We selected 34 genes based on NCCN (v1.2023) and European Association of Urology (EAU, v2.0) clinical guidelines and literature [<span>2, 3</span>] (Supplementary Table S2). We found 268 variants in 26 of these genes (<i>APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1/2, CDH1, CDK4, CHEK2, DICER1, MLH1, MSH2/3/6, MUTYH, NF1, PMS2, POLD1, POLE, PTEN, RAD51C/D, SMAD4, STK11</i> and <i>TP53</i>), most of which were intronic (91.4%) and/or unreported (84.3%) (Supplementary Figure S3 and Supplementary Table S3). In addition, genome-wide analysis of high-impact variants revealed only four mutations affecting the major isoforms of the <i>ANAPC1</i>, <i>HIBCH</i>, and <i>MOK</i>, but none of these genes have been previously reported in PC (Supplementary Table S4). Interestingly, despite being high-risk cancer patients, the individuals in the present study's family did not show any pathogenic mutations in the genes specified by clinical guidelines. Furthermore, this is added to the growing evidence for the potential of non-coding mutations, both near-exonic and deep-intronic mutations, in carcinogenesis. There is already evidence of how known tumor suppressor genes are affected by intronic mutations [<span>4</span>]. Exome analysis also reported ten identical mutations in three genes, one in <i>AXIN2</i>, two in <i>DICER1</i> and seven in <i>BARD1</i>, in all PC patients (Supplementary Table S3), suggesting that these mutations may be responsible for the development of cancer in this family. Among th
亲爱的编辑，遗传性前列腺癌（PC）占所有 PC 病例的 5%-10%。众所周知，有家族病史的男性罹患前列腺癌的风险会增加，这通常是由种系突变引起的，因此临床指南中提到了用于识别高危人群的各种基因。然而，涉及多个单核苷酸多态性（SNP）的复杂遗传模式使其成为一种遗传异质性疾病，基因检测仍处于早期阶段。美国国家综合癌症网络（NCCN）等机构制定的现行指南不足以对所有 PC 患者进行识别和分层[1]。为了改善家族性 PC 的检测和筛查，我们报告了一个由 7 名成员（2 名健康、4 名 PC 和 1 名乳腺癌）组成的 PC 多病例家族（图 1A，补充表 S1）的多组学分析（补充图 S1-S2），该分析结合了外显子组、转录组和表观基因组分析（全 DNA 甲基化和小 RNA 测序），为迄今为止对遗传性 PC 的了解提供了一个独特的视角。每个家族都是一个小的遗传单元，与病理相同但遗传起源不同的其他家族有显著差异。因此，个体化研究可能是揭示这种疾病异质性的关键。我们根据 NCCN（v1.2023）和欧洲泌尿外科协会（EAU，v2.0）的临床指南和文献[2, 3]选择了 34 个基因（补充表 S2）。我们在其中 26 个基因（APC、ATM、AXIN2、BARD1、BMPR1A、BRCA1/2、CDH1、CDK4、CHEK2、DICER1、MLH1、MSH2/3/6、MUTYH、NF1、PMS2、POLD1、POLE、PTEN、RAD51C/D、SMAD4、STK11 和 TP53）中发现了 268 个变异，其中大部分为内含子（91.4%）和/或未报告（84.3%）（补充图 S3 和补充表 S3）。此外，对高影响变异的全基因组分析显示，只有 4 个突变影响到 ANAPC1、HIBCH 和 MOK 的主要同工酶，但这些基因以前都未在 PC 中报道过（补充表 S4）。有趣的是，尽管是高危癌症患者，本研究中的家族成员并没有出现临床指南中规定的致病基因突变。此外，越来越多的证据表明，非编码突变（包括近外显子突变和深内显子突变）在致癌过程中具有潜在作用。已有证据表明，已知的肿瘤抑制基因会受到内含子突变的影响[4]。外显子组分析还报告了所有 PC 患者中三个基因的十个相同突变，其中一个在 AXIN2，两个在 DICER1，七个在 BARD1（补充表 S3），这表明这些突变可能是该家族癌症发生的原因。在这十个相同的突变中，BARD1 中的三个突变（c.2001+66A>C、c.1811-69T>C 和 c.1811-77A>G）和 AXIN2 中的一个突变（c.-116-1330C>G）在欧洲人群中的频率低于 0.05。接下来，我们主要关注与β-catenin通路相互作用的新型遗传标记--AXIN2和DICER1，但也提到了其他相关数据。AXIN2和APC作为β-catenin破坏复合体的一部分，在Wnt信号通路中发挥着重要作用。AXIN2 和 APC 作为 β-catenin 破坏复合体的一部分，在 Wnt 信号通路中发挥着重要作用。部分或完全丧失这些基因的活性会导致 β-catenin 活性增加，从而导致靶基因异常激活，促进细胞增殖和存活（图 1B）[5]。最近，DICER1也被认为是β-catenin的靶基因。此外，在肝脏肿瘤中，DICER1 的突变与 β-catenin 的突变相关，导致其被激活。在子宫内膜样癌和分化良好的胎儿肺腺癌中也观察到了这两个基因同时发生突变的现象[6]。基于这一科学背景，我们在所研究的癌症患者中发现了相同的β-catenin突变（c.*13-8742G>A）。这种内含子突变出现在该基因的无义介导衰变异构体（CTNNB1-212）中，可能会影响该基因的调控和质量控制，防止转录错误[7]。APC 或 β-catenin 突变导致的 Wnt 信号激活已在多种癌症类型中被观察到，在高达 22% 的阉割耐药 PC 中也被观察到 [8]。转录组研究显示，β-catenin 的靶基因 ALDH1A1 明显过表达（P 值 = 2.816 × 10-5，Log2-fold change (logFC) = 1.638）[9]，而β-catenin 的表达与 PC 进展过程中的致癌转化有关（补充表 S5）。据观察，KIFC1、RRM2 和 CYP1B1 的过表达可激活 Wnt 信号通路。
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