Pub Date : 2024-11-12DOI: 10.1158/0008-5472.can-24-1263
Terrance J. Haanen, Sophie Boock, Catherine G. Callahan, Irene Peris, Kaitlin P. Zawacki, Brynne Raines, Charles A. Nino, Brian Tran, Alexis Harold, Gabrielle Hodges Onishi, Matthew Hinderman, Amanda Dowdican, Wei Huang, Derek J. Taylor, Sarah E. Taylor, Mark W. Jackson, Analisa DiFeo, Caitlin M. O'Connor, Goutham Narla
Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.
{"title":"Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer","authors":"Terrance J. Haanen, Sophie Boock, Catherine G. Callahan, Irene Peris, Kaitlin P. Zawacki, Brynne Raines, Charles A. Nino, Brian Tran, Alexis Harold, Gabrielle Hodges Onishi, Matthew Hinderman, Amanda Dowdican, Wei Huang, Derek J. Taylor, Sarah E. Taylor, Mark W. Jackson, Analisa DiFeo, Caitlin M. O'Connor, Goutham Narla","doi":"10.1158/0008-5472.can-24-1263","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1263","url":null,"abstract":"Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"127 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1158/0008-5472.can-24-0591
Tae Hyun Bae, Ki Woon Sung, Tri M. Pham, Abdo J. Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Ha Kyoung Kwon, Yeon Sung Son, Dongping Shi, Steven Kregel, Elisabeth I. Heath, Michael L. Cher, Yong Tae Kwon, Hyeong-Reh C. Kim
Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.
基因改变在各种人类疾病，尤其是癌症中起着举足轻重的作用。雄激素受体（AR）是驱动前列腺癌（PCa）各阶段进展的关键转录因子。目前的 AR 靶向疗法利用竞争性 AR 拮抗剂或通路抑制剂。然而，由于AR突变和AR剪接变体（如AR-v7），常常会出现耐药性。为了克服这一问题，我们利用创新性蛋白质降解技术平台 AUTOphagy-TArgeting Chimera（AUTOTAC）开发了一种 AR 降解剂 ATC-324。ATC-324 由 AR 抑制剂恩杂鲁胺和自噬受体 p62/SQSTM1 的配体 YT 6-2 组成，前者是目标结合配体，后者是自噬靶向配体。ATC-324 可诱导 AR/p62 复合物的形成，从而导致 AR 的自噬-溶酶体降解。重要的是，ATC-324 能有效降解 PCa 中经常检测到的 AR 突变体，并以异源二聚体的形式与全长 AR 共同降解 AR-v7。ATC-324 可降低核 AR 水平，下调 AR 和 AR-v7 的靶基因表达，从而对 AR 阳性 PCa 细胞产生细胞毒性。我们还提供了 ATC-324 在体内和体外骨器官培养中的治疗潜力证据。此外，ATC-324 对恩扎鲁胺耐药的 PCa 细胞仍然有效。这些结果证明了 AUTOTAC 平台的潜力，它可以靶向以前被认为是不可药用的蛋白质，并克服某些耐药机制。
{"title":"An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer","authors":"Tae Hyun Bae, Ki Woon Sung, Tri M. Pham, Abdo J. Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Ha Kyoung Kwon, Yeon Sung Son, Dongping Shi, Steven Kregel, Elisabeth I. Heath, Michael L. Cher, Yong Tae Kwon, Hyeong-Reh C. Kim","doi":"10.1158/0008-5472.can-24-0591","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0591","url":null,"abstract":"Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1158/0008-5472.can-24-1817
Simeng Wang, Jia-Cheng Lai, Yu Li, Chengfang Tang, Jiajia Lu, Min Han, Xianjiang Ye, Lina Jia, Wei Cui, Jingyu Yang, Chunfu Wu, Lihui Wang
Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.
{"title":"Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR Mutant Non-Small Cell Lung Cancer","authors":"Simeng Wang, Jia-Cheng Lai, Yu Li, Chengfang Tang, Jiajia Lu, Min Han, Xianjiang Ye, Lina Jia, Wei Cui, Jingyu Yang, Chunfu Wu, Lihui Wang","doi":"10.1158/0008-5472.can-24-1817","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1817","url":null,"abstract":"Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1158/0008-5472.can-24-1703
Abigail Shea, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Raquel Manzano Garcia, Wendy Greenwood, Martin O’Reilly, Dimitra Georgopoulou, Maurizio Callari, Giulia Lerda, Sophia Wix, Agnese Giovannetti, Riccardo Masina, Elham Esmaeilishirazifard, Wei Cope, Alistair G. Martin, Ai Nagano, Lisa Young, Steven Kupczak, Yi Cheng, Helen Bardwell, Elena Provenzano, Justine Kane, Jonny Lay, Louise Grybowicz, Karen McAdam, Carlos Caldas, Jean Abraham, Oscar M. Rueda, Alejandra Bruna
The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.
{"title":"Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer","authors":"Abigail Shea, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Raquel Manzano Garcia, Wendy Greenwood, Martin O’Reilly, Dimitra Georgopoulou, Maurizio Callari, Giulia Lerda, Sophia Wix, Agnese Giovannetti, Riccardo Masina, Elham Esmaeilishirazifard, Wei Cope, Alistair G. Martin, Ai Nagano, Lisa Young, Steven Kupczak, Yi Cheng, Helen Bardwell, Elena Provenzano, Justine Kane, Jonny Lay, Louise Grybowicz, Karen McAdam, Carlos Caldas, Jean Abraham, Oscar M. Rueda, Alejandra Bruna","doi":"10.1158/0008-5472.can-24-1703","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1703","url":null,"abstract":"The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent in HCC, and elevated levels of CSTF2 correlated with poor patient prognosis. While CSTF2 inhibition did not suppress HCC growth under non-stress conditions, it supported tolerance and survival of HCC cells under hypoxic conditions. Mechanistically, CSTF2 increased PGK1 protein production to enhance glycolysis, thereby sustaining the energy supply under hypoxic conditions. CSTF2 shortened the 3' untranslated region (3' UTR) of phosphoglycerate kinase 1 (PGK1) pre-mRNA by binding near the proximal polyadenylation site (pPAS). This shortening led to a loss of N6-methyladenosine (m6A) modification sites that are bound by YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) and increase degradation of PGK1 mRNA. Concurrently, hypoxia increased m6A modification of PGK1 mRNA near the pPAS that was recognized by the YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), which recruited CSTF2 to enhance the shortening of the PGK1 3’-UTR. A small molecule screen identified masitinib as an inhibitor of CSTF2. Masitinib counteracted PGK1 upregulation by CSTF2 and suppressed the growth of HCC xenograft and patient-derived organoid models. In conclusion, this study revealed a function of CSTF2 in supporting HCC survival under hypoxia conditions through m6A modification evasion and metabolic reprogramming, indicating inhibiting CSTF2 may overcome hypoxia tolerance in HCC.
{"title":"CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis","authors":"Qiangnu Zhang, Yusen Zhang, Chuli Fu, Xiaoyan He, Zuotian Huang, Geyan Wu, Teng Wei, Wen Jin, Lesen Yan, Meilong Wu, Gongze Peng, LinLan Fan, Mingyue Li, Yuehua Guo, Jiangang Bi, Yu Bai, Stephanie Roessler, Guang-Rong Yan, Liping Liu","doi":"10.1158/0008-5472.can-24-2283","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2283","url":null,"abstract":"Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent in HCC, and elevated levels of CSTF2 correlated with poor patient prognosis. While CSTF2 inhibition did not suppress HCC growth under non-stress conditions, it supported tolerance and survival of HCC cells under hypoxic conditions. Mechanistically, CSTF2 increased PGK1 protein production to enhance glycolysis, thereby sustaining the energy supply under hypoxic conditions. CSTF2 shortened the 3' untranslated region (3' UTR) of phosphoglycerate kinase 1 (PGK1) pre-mRNA by binding near the proximal polyadenylation site (pPAS). This shortening led to a loss of N6-methyladenosine (m6A) modification sites that are bound by YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) and increase degradation of PGK1 mRNA. Concurrently, hypoxia increased m6A modification of PGK1 mRNA near the pPAS that was recognized by the YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), which recruited CSTF2 to enhance the shortening of the PGK1 3’-UTR. A small molecule screen identified masitinib as an inhibitor of CSTF2. Masitinib counteracted PGK1 upregulation by CSTF2 and suppressed the growth of HCC xenograft and patient-derived organoid models. In conclusion, this study revealed a function of CSTF2 in supporting HCC survival under hypoxia conditions through m6A modification evasion and metabolic reprogramming, indicating inhibiting CSTF2 may overcome hypoxia tolerance in HCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1158/0008-5472.can-24-0880
Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G. Duda, Anand T.N. Kumar
Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.
{"title":"Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity","authors":"Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G. Duda, Anand T.N. Kumar","doi":"10.1158/0008-5472.can-24-0880","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0880","url":null,"abstract":"Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.
{"title":"Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity","authors":"Xiaolin Wang, Hui Wang, Zhengjing Lu, Xiangjun Liu, Wenjia Chai, Wei Wang, Jun Feng, Shen Yang, Wei Yang, Haiyan Cheng, Chenghao Chen, Shihan Zhang, Nian Sun, Qiaoyin Liu, Qiliang Li, Wenqi Song, Fang Jin, Qi Zeng, Shengcai Wang, Yan Su, Huanmin Wang, Xin Ni, Jingang Gui","doi":"10.1158/0008-5472.can-24-1509","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1509","url":null,"abstract":"The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1158/0008-5472.can-24-4054
Benjamin Izar, Minah Kim
Melanoma brain metastasis is associated with high morbidity and mortality and remains a major clinical challenge. Despite recent successes with combination immune checkpoint inhibitors (ICI) in the treatment of affected patients, the mechanistic underpinnings of T cell entry and response to these drugs in brain metastasis are poorly understood. Using real-time intravital microscopy, Messmer and colleagues identified peritumoral venous vessels (PVVs) as critical sites for T cell entry into brain metastases, a process accelerated by ICI treatment. The expression of intercellular adhesion molecule 1 (ICAM-1) on PVVs was found to be important for T cell recruitment in pre-clinical models and associated with increased T cell infiltration in human brain metastatic lesions. This study highlights PVVs as key vascular entry points for T cells into brain metastases, laying the foundation for enhancing the efficacy of cancer immunotherapies.
黑色素瘤脑转移与高发病率和高死亡率有关，仍然是一项重大的临床挑战。尽管最近联合免疫检查点抑制剂（ICI）在治疗受影响患者方面取得了成功，但人们对T细胞进入脑转移瘤并对这些药物产生反应的机理基础知之甚少。Messmer 及其同事利用实时体视显微镜确定了瘤周静脉血管 (PVV) 是 T 细胞进入脑转移瘤的关键部位，ICI 治疗加速了这一过程。研究发现，PVV 上细胞间粘附分子 1（ICAM-1）的表达对临床前模型中 T 细胞的招募非常重要，而且与人类脑转移病灶中 T 细胞浸润的增加有关。这项研究强调了 PVV 是 T 细胞进入脑转移灶的关键血管入口，为提高癌症免疫疗法的疗效奠定了基础。
{"title":"Peritumoral Venous Vessels: Autobahn and Portal for T cells to Melanoma Brain Metastasis","authors":"Benjamin Izar, Minah Kim","doi":"10.1158/0008-5472.can-24-4054","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4054","url":null,"abstract":"Melanoma brain metastasis is associated with high morbidity and mortality and remains a major clinical challenge. Despite recent successes with combination immune checkpoint inhibitors (ICI) in the treatment of affected patients, the mechanistic underpinnings of T cell entry and response to these drugs in brain metastasis are poorly understood. Using real-time intravital microscopy, Messmer and colleagues identified peritumoral venous vessels (PVVs) as critical sites for T cell entry into brain metastases, a process accelerated by ICI treatment. The expression of intercellular adhesion molecule 1 (ICAM-1) on PVVs was found to be important for T cell recruitment in pre-clinical models and associated with increased T cell infiltration in human brain metastatic lesions. This study highlights PVVs as key vascular entry points for T cells into brain metastases, laying the foundation for enhancing the efficacy of cancer immunotherapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"95 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1158/0008-5472.CAN-23-3074
Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang
The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.
{"title":"FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis.","authors":"Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang","doi":"10.1158/0008-5472.CAN-23-3074","DOIUrl":"10.1158/0008-5472.CAN-23-3074","url":null,"abstract":"<p><p>The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3574-3588"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757222","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}
Pub Date : 2024-11-04DOI: 10.1158/0008-5472.CAN-23-3574
Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi
MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.
{"title":"Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.","authors":"Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi","doi":"10.1158/0008-5472.CAN-23-3574","DOIUrl":"10.1158/0008-5472.CAN-23-3574","url":null,"abstract":"<p><p>MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3629-3639"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975090","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}
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