Pub Date : 2025-02-12DOI: 10.1158/0008-5472.CAN-24-2492
Shuyan Zhou, Yi Zhang, Julie Belmar, Chunyan Hou, Yaqin Zhang, Changmin Peng, Yunxiao Meng, Zhuqing Li, Muhammad Jameel Mughal, Yanjun Gao, Edward Seto, Min Shen, Matthew D Hall, Junfeng Ma, Cynthia X Ma, Shunqiang Li, Wenge Zhu
Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial in regulating cell cycle progression and cancer development. Targeting CDK4/6 has shown considerable promise in treating various cancers, including breast cancer. Despite significant therapeutic efficacy, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial hurdle in clinical practice. Using a co-culture system, cytokine array, and quantitative high-throughput combinatorial screening (qHTCS), we discovered a mechanism by which the RUNX1-PDGF-BB axis regulates palbociclib resistance in breast cancer cells. Specifically, RUNX1 functioned as a transcription factor to drive expression of PDGF-BB, leading to resistance to palbociclib by enhancing the Akt pathway and suppressing senescence. Furthermore, in resistant cells, RUNX1 was O-GlcNAcylated at serine 252 (S252) by OGT, resulting in the stabilization of RUNX1 by preventing ubiquitin-mediated degradation. Inhibition of the RUNX1-PDGF-BB axis by specific inhibitors overcame palbociclib resistance both in vitro and in vivo. Notably, the RUNX1-PDGF-BB axis was upregulated in resistant patient-derived xenograft (PDX) lines and in breast cancer patients following treatment with CDK4/6i. These findings not only unveil O-GlcNAcylation-mediated activation of a RUNX1-PDGF-BB pathway as a driver of palbociclib resistance but also provide clinical evidence supporting the repurposing of FDA-approved PDGFR inhibitors as a therapeutic strategy to treat CDK4/6i-resistant breast cancer patients.
{"title":"Stabilization of RUNX1 Induced by O-GlcNAcylation Promotes PDGF-BB-Mediated Resistance to CDK4/6 Inhibitors in Breast Cancer.","authors":"Shuyan Zhou, Yi Zhang, Julie Belmar, Chunyan Hou, Yaqin Zhang, Changmin Peng, Yunxiao Meng, Zhuqing Li, Muhammad Jameel Mughal, Yanjun Gao, Edward Seto, Min Shen, Matthew D Hall, Junfeng Ma, Cynthia X Ma, Shunqiang Li, Wenge Zhu","doi":"10.1158/0008-5472.CAN-24-2492","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2492","url":null,"abstract":"<p><p>Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial in regulating cell cycle progression and cancer development. Targeting CDK4/6 has shown considerable promise in treating various cancers, including breast cancer. Despite significant therapeutic efficacy, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial hurdle in clinical practice. Using a co-culture system, cytokine array, and quantitative high-throughput combinatorial screening (qHTCS), we discovered a mechanism by which the RUNX1-PDGF-BB axis regulates palbociclib resistance in breast cancer cells. Specifically, RUNX1 functioned as a transcription factor to drive expression of PDGF-BB, leading to resistance to palbociclib by enhancing the Akt pathway and suppressing senescence. Furthermore, in resistant cells, RUNX1 was O-GlcNAcylated at serine 252 (S252) by OGT, resulting in the stabilization of RUNX1 by preventing ubiquitin-mediated degradation. Inhibition of the RUNX1-PDGF-BB axis by specific inhibitors overcame palbociclib resistance both in vitro and in vivo. Notably, the RUNX1-PDGF-BB axis was upregulated in resistant patient-derived xenograft (PDX) lines and in breast cancer patients following treatment with CDK4/6i. These findings not only unveil O-GlcNAcylation-mediated activation of a RUNX1-PDGF-BB pathway as a driver of palbociclib resistance but also provide clinical evidence supporting the repurposing of FDA-approved PDGFR inhibitors as a therapeutic strategy to treat CDK4/6i-resistant breast cancer patients.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398061","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 : 2025-02-11DOI: 10.1158/0008-5472.can-24-0401
Zuzanna Nowicka, Frederika Rentzeperis, Vural Tagal, Jamie K. Teer, Didem Ilter, Richard J. Beck, Jackson P. Cole, Ana M. Forero Pinto, Joanne D. Tejero, Elisa Scanu, Thomas Veith, William Dominguez-Viqueira, Konstantin Maksin, Francisco M. Carrillo-Perez, Olivier Gevaert, Xiaonan Xu, Florian A. Karreth, Mahmoud A. Abdalah, Giada Fiandaca, Stefano Pasetto, Sandhya Prabhakaran, Andrew Schultz, Awino Maureiq E. Ojwang’, Jill S. Barnholtz-Sloan, Joaquim M. Farinhas, Ana P. Gomes, Parag Katira, Noemi Andor
Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multi-omics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high ploidy cells transition faster from oxidative phosphorylation to glycolysis than low ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence.
{"title":"Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma","authors":"Zuzanna Nowicka, Frederika Rentzeperis, Vural Tagal, Jamie K. Teer, Didem Ilter, Richard J. Beck, Jackson P. Cole, Ana M. Forero Pinto, Joanne D. Tejero, Elisa Scanu, Thomas Veith, William Dominguez-Viqueira, Konstantin Maksin, Francisco M. Carrillo-Perez, Olivier Gevaert, Xiaonan Xu, Florian A. Karreth, Mahmoud A. Abdalah, Giada Fiandaca, Stefano Pasetto, Sandhya Prabhakaran, Andrew Schultz, Awino Maureiq E. Ojwang’, Jill S. Barnholtz-Sloan, Joaquim M. Farinhas, Ana P. Gomes, Parag Katira, Noemi Andor","doi":"10.1158/0008-5472.can-24-0401","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0401","url":null,"abstract":"Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multi-omics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high ploidy cells transition faster from oxidative phosphorylation to glycolysis than low ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393507","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 : 2025-02-11DOI: 10.1158/0008-5472.can-24-1793
Danyyl Ippolitov, Yi-Han Lin, Jeremy Spence, Aleksandra Glogowska, Thatchawan Thanasupawat, Jason Beiko, Marc R. Del Bigio, Xin Xu, Amy Q. Wang, Darian Williams, Raul Calvo, Abhijeet Kapoor, Juan J. Marugan, Mark J. Henderson, Thomas Klonisch, Sabine Hombach-Klonisch
Brain metastasis occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in vivo models for HER2+ BCBM has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. Here, we generated and characterized a luminal B HER2+ BCBM cell model (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ErbB receptors (ErbB1-4) and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), an ErbB3/ErbB4 ligand that is abundantly expressed in the brain, abrogated lapatinib-induced apoptosis in HER2+ BCBM94 and BT474 models. ErbB3 signaling pathways that involved PI3K-AKT and the phosphorylation of BAD at serine 136 to prevent apoptosis were essential for NRG1-induced survival. High throughput RTKi screening identified the brain-penetrant pan-ErbB inhibitor poziotinib as a highly potent compound that reduced cell viability in HER2+ BCBM in the presence of NRG1. Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2+ brain tumors in vivo. In conclusion, this study established a patient-derived HER2+ BCBM model and identified poziotinib as highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ BCBM.
{"title":"The Brain-Penetrant Pan ErbB Inhibitor Poziotinib Effectively Targets HER2+ Breast Cancer Brain Metastases","authors":"Danyyl Ippolitov, Yi-Han Lin, Jeremy Spence, Aleksandra Glogowska, Thatchawan Thanasupawat, Jason Beiko, Marc R. Del Bigio, Xin Xu, Amy Q. Wang, Darian Williams, Raul Calvo, Abhijeet Kapoor, Juan J. Marugan, Mark J. Henderson, Thomas Klonisch, Sabine Hombach-Klonisch","doi":"10.1158/0008-5472.can-24-1793","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1793","url":null,"abstract":"Brain metastasis occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in vivo models for HER2+ BCBM has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. Here, we generated and characterized a luminal B HER2+ BCBM cell model (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ErbB receptors (ErbB1-4) and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), an ErbB3/ErbB4 ligand that is abundantly expressed in the brain, abrogated lapatinib-induced apoptosis in HER2+ BCBM94 and BT474 models. ErbB3 signaling pathways that involved PI3K-AKT and the phosphorylation of BAD at serine 136 to prevent apoptosis were essential for NRG1-induced survival. High throughput RTKi screening identified the brain-penetrant pan-ErbB inhibitor poziotinib as a highly potent compound that reduced cell viability in HER2+ BCBM in the presence of NRG1. Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2+ brain tumors in vivo. In conclusion, this study established a patient-derived HER2+ BCBM model and identified poziotinib as highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ BCBM.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"99 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393508","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 : 2025-02-11DOI: 10.1158/0008-5472.can-25-0479
Lisa Martina, Michał Małszycki, Tuğçe Aktaş
The complex environment of the mammalian nucleus is compartmentalized into functional units by membraneless organelles. Recent advancements have elevated nuclear speckles, one of the most prominent nuclear condensates, to a central role in gene expression regulation. In their recent paper, Alexander and colleagues provide insights into the involvement of nuclear speckles in cancer progression. They identify two signatures of speckle transcriptome that stratify human cancers and, in the case of the clear cell renal cell carcinoma (ccRC), strongly correlate with drug response and ultimately with patient’s survival. These signatures correspond to different morphological states of nuclear speckles and influence speckle-regulated gene expression. A deeper look into transcriptional regulation allowed the authors to identify an amino acid sequence which enables the central transcription factor responsible of ccRC oncogenesis to bring its chromatin target into nuclear speckle proximity. The findings provide new insights into the intricacies of nuclear speckle biology and offer new avenues for understanding cancer progression and developing targeted therapies.
{"title":"Distinct states of Nuclear Speckles emerge as new predictors of cancer prognosis","authors":"Lisa Martina, Michał Małszycki, Tuğçe Aktaş","doi":"10.1158/0008-5472.can-25-0479","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0479","url":null,"abstract":"The complex environment of the mammalian nucleus is compartmentalized into functional units by membraneless organelles. Recent advancements have elevated nuclear speckles, one of the most prominent nuclear condensates, to a central role in gene expression regulation. In their recent paper, Alexander and colleagues provide insights into the involvement of nuclear speckles in cancer progression. They identify two signatures of speckle transcriptome that stratify human cancers and, in the case of the clear cell renal cell carcinoma (ccRC), strongly correlate with drug response and ultimately with patient’s survival. These signatures correspond to different morphological states of nuclear speckles and influence speckle-regulated gene expression. A deeper look into transcriptional regulation allowed the authors to identify an amino acid sequence which enables the central transcription factor responsible of ccRC oncogenesis to bring its chromatin target into nuclear speckle proximity. The findings provide new insights into the intricacies of nuclear speckle biology and offer new avenues for understanding cancer progression and developing targeted therapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"55 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393506","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 : 2025-02-11DOI: 10.1158/0008-5472.can-24-1757
Jonathan M. DeLiberty, Mallory K. Roach, Clint A. Stalnecker, Ryan Robb, Elyse G. Schechter, Noah L. Pieper, Khalilah E. Taylor, Lily M. Pita, Runying Yang, Scott Bang, Kristina Drizyte-Miller, Sarah E. Ackermann, Sheila R. Nicewarner Peña, Elisa Baldelli, Sophia M. Min, David H. Drewry, Emanuel F. Petricoin, John P. Morris, Channing J. Der, Adrienne D. Cox, Kirsten L. Bryant
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth. However, CQ is limited in terms of specificity and potency. To find alternative anti-autophagy strategies, here we performed a CRISPR-Cas9 loss-of-function screen in PDAC cell lines that identified the lipid kinase PIKfyve as a growth-promoting gene. PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment. PIKfyve inhibition caused lysosomal dysfunction, reduced autophagic flux, and led to the accumulation of autophagy-related proteins. Furthermore, PIKfyve inhibition blocked the compensatory increases in autophagic flux associated both with MEK inhibition and with direct RAS inhibition. Accordingly, combined inhibition of PIKfyve and the RAS-MAPK pathway showed robust growth suppression across a panel of KRAS-mutant PDAC models. Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC.
{"title":"Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve is a Therapeutic Strategy for Pancreatic Cancer","authors":"Jonathan M. DeLiberty, Mallory K. Roach, Clint A. Stalnecker, Ryan Robb, Elyse G. Schechter, Noah L. Pieper, Khalilah E. Taylor, Lily M. Pita, Runying Yang, Scott Bang, Kristina Drizyte-Miller, Sarah E. Ackermann, Sheila R. Nicewarner Peña, Elisa Baldelli, Sophia M. Min, David H. Drewry, Emanuel F. Petricoin, John P. Morris, Channing J. Der, Adrienne D. Cox, Kirsten L. Bryant","doi":"10.1158/0008-5472.can-24-1757","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1757","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth. However, CQ is limited in terms of specificity and potency. To find alternative anti-autophagy strategies, here we performed a CRISPR-Cas9 loss-of-function screen in PDAC cell lines that identified the lipid kinase PIKfyve as a growth-promoting gene. PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment. PIKfyve inhibition caused lysosomal dysfunction, reduced autophagic flux, and led to the accumulation of autophagy-related proteins. Furthermore, PIKfyve inhibition blocked the compensatory increases in autophagic flux associated both with MEK inhibition and with direct RAS inhibition. Accordingly, combined inhibition of PIKfyve and the RAS-MAPK pathway showed robust growth suppression across a panel of KRAS-mutant PDAC models. Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393510","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 : 2025-02-04DOI: 10.1158/0008-5472.can-24-2289
Chenyang Zhang, Yan-Yan Chen, Shuyu Chen, Yunzhe Wang, Yifan Yuan, Xiwen Yang, Wei Hu, Bo Chen, Zengxin Qi, Jason T. Huse, Yun Liu, Bo Wen, Xiuping Liu, Leng Han, Yuxiang Wang, Zhao Zhang
Non-coding RNA transcribed from active enhancers, known as enhancer RNA (eRNA), is a critical element in gene regulation with a highly specific expression pattern in the regulatory networks of tumor-infiltrating cells. Therefore, eRNA signatures could potentially be applied to represent anti-tumor immune cells and to improve cancer immunotherapy. Herein, we identified thousands of eRNAs that were significantly correlated with infiltrating immune cell abundance in more than 10,000 patient samples across a variety of cancer types. The expression of these eRNAs was mediated by transcription factors with high expression in anti-tumor immune cells, as identified through single-cell assays. An eRNA immunotherapy signature (eRIS) developed using the anti-tumor eRNAs was highly associated with the objective response rate (ORR) of immunotherapy and was elevated in patients who benefited from immune checkpoint blockade (ICB) treatment. In comparison with a signature based on protein-coding genes, the eRIS was more effective in predicting the response to immunotherapy. Integration of the eRIS with pharmacogenomic data revealed hundreds of anti-cancer drugs that have the potential to enhance immunotherapy efficacy. Finally, treatment of a mouse model of IDH mutant glioma with the histone deacetylase inhibitor vorinostat improved the effects of anti-PD-1 immunotherapy through increased abundance of infiltrating immune cells. Taken together, this study developed an eRIS with demonstrated efficacy in predicting immunotherapy response and used the eRIS to identify a series of effective combination drugs, thus highlighting the clinical utility of the eRIS in immunotherapy enhancement.
{"title":"Characterization of an Enhancer RNA Signature Reveals Treatment Strategies for Improving Immunotherapy Efficacy in Cancer","authors":"Chenyang Zhang, Yan-Yan Chen, Shuyu Chen, Yunzhe Wang, Yifan Yuan, Xiwen Yang, Wei Hu, Bo Chen, Zengxin Qi, Jason T. Huse, Yun Liu, Bo Wen, Xiuping Liu, Leng Han, Yuxiang Wang, Zhao Zhang","doi":"10.1158/0008-5472.can-24-2289","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2289","url":null,"abstract":"Non-coding RNA transcribed from active enhancers, known as enhancer RNA (eRNA), is a critical element in gene regulation with a highly specific expression pattern in the regulatory networks of tumor-infiltrating cells. Therefore, eRNA signatures could potentially be applied to represent anti-tumor immune cells and to improve cancer immunotherapy. Herein, we identified thousands of eRNAs that were significantly correlated with infiltrating immune cell abundance in more than 10,000 patient samples across a variety of cancer types. The expression of these eRNAs was mediated by transcription factors with high expression in anti-tumor immune cells, as identified through single-cell assays. An eRNA immunotherapy signature (eRIS) developed using the anti-tumor eRNAs was highly associated with the objective response rate (ORR) of immunotherapy and was elevated in patients who benefited from immune checkpoint blockade (ICB) treatment. In comparison with a signature based on protein-coding genes, the eRIS was more effective in predicting the response to immunotherapy. Integration of the eRIS with pharmacogenomic data revealed hundreds of anti-cancer drugs that have the potential to enhance immunotherapy efficacy. Finally, treatment of a mouse model of IDH mutant glioma with the histone deacetylase inhibitor vorinostat improved the effects of anti-PD-1 immunotherapy through increased abundance of infiltrating immune cells. Taken together, this study developed an eRIS with demonstrated efficacy in predicting immunotherapy response and used the eRIS to identify a series of effective combination drugs, thus highlighting the clinical utility of the eRIS in immunotherapy enhancement.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125396","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 : 2025-02-04DOI: 10.1158/0008-5472.can-23-2796
Chuanjie Zhang, Jiawei Ding, Kiat Shenq Lim, Wenjie Zhou, Wenyu Miao, Siqi Wu, Hanqing Liu, Da Huang, Chufeng Chen, Hongchao He, Jun Xiao, Dan-feng Xu, Yan Shen, Hai Huang, Yi Gao
Ferroptosis inducers have shown therapeutic potential in prostate cancer (PCa), but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic crosstalk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. Here, we found that aberrant accumulation of jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis of PCa patients. Mechanistically, PCa-associated speckle type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer-promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6-ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated PCa selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple pre-clinical PCa models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated PCa to increase sensitivity to ferroptosis inducers.
{"title":"JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer","authors":"Chuanjie Zhang, Jiawei Ding, Kiat Shenq Lim, Wenjie Zhou, Wenyu Miao, Siqi Wu, Hanqing Liu, Da Huang, Chufeng Chen, Hongchao He, Jun Xiao, Dan-feng Xu, Yan Shen, Hai Huang, Yi Gao","doi":"10.1158/0008-5472.can-23-2796","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2796","url":null,"abstract":"Ferroptosis inducers have shown therapeutic potential in prostate cancer (PCa), but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic crosstalk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. Here, we found that aberrant accumulation of jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis of PCa patients. Mechanistically, PCa-associated speckle type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer-promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6-ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated PCa selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple pre-clinical PCa models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated PCa to increase sensitivity to ferroptosis inducers.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"61 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125459","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 : 2025-02-04DOI: 10.1158/0008-5472.can-24-0707
Brandon J. Metge, Li'an Williams, Courtney A. Swain, Dominique C. Hinshaw, Amr R. Elhamamsy, Dongquan Chen, Rajeev S. Samant, Lalita A. Shevde
Macrophages are important cellular components of the innate immune system, serving as the first line of immune defense. They are also among the first immune cells to be reprogrammed by the evolving tumor milieu into tumor-supportive macrophages that facilitate tumor progression and promote therapeutic evasion. Here, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes, indicating that this is an early event that is maintained in the tumor tissue. Furthermore, following treatment with irradiation or chemotherapy, breast tumors featured an abundance of tumor-supporting macrophages that displayed an enrichment of signatures of ribosomal RNA expression and ribosome biosynthesis. Consistently, rRNA synthesis was increased in tumor-supportive macrophages. In preclinical models of mammary cancer, a low dose of the RNA biogenesis inhibitor BMH-21 converted pro-tumor macrophages to tumor-suppressive macrophages and supported an inflammatory tumor microenvironment. Inhibition of rRNA transcription stimulated a nucleolar stress response that activated the p53 and NF-κB pathways, which orchestrated impaired ribosome biogenesis checkpoint signaling that induced an inflammatory program in macrophages. Finally, inhibiting ribosome biogenesis augmented the effectiveness of neoadjuvant therapy. Together, these findings provide evidence that ribosome biogenesis is a targetable dependency to reprogram the tumor immune microenvironment.
{"title":"Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression","authors":"Brandon J. Metge, Li'an Williams, Courtney A. Swain, Dominique C. Hinshaw, Amr R. Elhamamsy, Dongquan Chen, Rajeev S. Samant, Lalita A. Shevde","doi":"10.1158/0008-5472.can-24-0707","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0707","url":null,"abstract":"Macrophages are important cellular components of the innate immune system, serving as the first line of immune defense. They are also among the first immune cells to be reprogrammed by the evolving tumor milieu into tumor-supportive macrophages that facilitate tumor progression and promote therapeutic evasion. Here, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes, indicating that this is an early event that is maintained in the tumor tissue. Furthermore, following treatment with irradiation or chemotherapy, breast tumors featured an abundance of tumor-supporting macrophages that displayed an enrichment of signatures of ribosomal RNA expression and ribosome biosynthesis. Consistently, rRNA synthesis was increased in tumor-supportive macrophages. In preclinical models of mammary cancer, a low dose of the RNA biogenesis inhibitor BMH-21 converted pro-tumor macrophages to tumor-suppressive macrophages and supported an inflammatory tumor microenvironment. Inhibition of rRNA transcription stimulated a nucleolar stress response that activated the p53 and NF-κB pathways, which orchestrated impaired ribosome biogenesis checkpoint signaling that induced an inflammatory program in macrophages. Finally, inhibiting ribosome biogenesis augmented the effectiveness of neoadjuvant therapy. Together, these findings provide evidence that ribosome biogenesis is a targetable dependency to reprogram the tumor immune microenvironment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125444","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 : 2025-02-01DOI: 10.1158/0008-5472.can-24-3879
Hannah E. Trembath, Philip M. Spanheimer
Racial disparities in cancer outcomes are well documented across tumor types. For patients with breast cancer, Black women are more likely to present with more aggressive molecular features and more likely to die from disease, even after accounting for those features. Recent efforts have been aimed at developing translational model systems for precision medicine strategies, and a major focus has been on patient-derived organoids. Organoids allow for robust in vitro experimental platforms, including drug and CRISPR screens while maintaining more complex cancer and tumor microenvironment subpopulations than cell lines. For results that are broadly translationally relevant, it is important that cancer models are derived from the spectrum of human disease and humans with disease. In this issue of Cancer Research, Madorsky Rowdo and colleagues derive breast cancer organoids from patients with African ancestry and use CRISPR-Cas9 screens to identify novel therapeutic vulnerabilities. These findings demonstrate the promise of representative cancer model systems to facilitate discoveries that are most likely to translate to improved therapy for all patients. See related article by Madorsky Rowdo et al., p. 551
{"title":"In Search of Representative Translational Cancer Model Systems","authors":"Hannah E. Trembath, Philip M. Spanheimer","doi":"10.1158/0008-5472.can-24-3879","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3879","url":null,"abstract":"Racial disparities in cancer outcomes are well documented across tumor types. For patients with breast cancer, Black women are more likely to present with more aggressive molecular features and more likely to die from disease, even after accounting for those features. Recent efforts have been aimed at developing translational model systems for precision medicine strategies, and a major focus has been on patient-derived organoids. Organoids allow for robust in vitro experimental platforms, including drug and CRISPR screens while maintaining more complex cancer and tumor microenvironment subpopulations than cell lines. For results that are broadly translationally relevant, it is important that cancer models are derived from the spectrum of human disease and humans with disease. In this issue of Cancer Research, Madorsky Rowdo and colleagues derive breast cancer organoids from patients with African ancestry and use CRISPR-Cas9 screens to identify novel therapeutic vulnerabilities. These findings demonstrate the promise of representative cancer model systems to facilitate discoveries that are most likely to translate to improved therapy for all patients. See related article by Madorsky Rowdo et al., p. 551","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"157 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072484","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 : 2025-02-01DOI: 10.1158/0008-5472.CAN-23-4027
Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech
Tumor-associated macrophages (TAM) are a heterogeneous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment. In this study, we unveiled a mechanism by which scavenger receptor cluster of differentiation 36 (CD36) suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I IFN (IFNI) production, mirroring the inverse correlation between CD36 and IFNI response observed in patients with cancer. IFNI, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFNI signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacologic inhibition of CD36 to rejuvenate antitumor immunity. Significance: CD36 in tumor-associated macrophages mediates immunosuppression and can be targeted as a therapeutic avenue for stimulating interferon production and increasing the efficacy of immunotherapy.
肿瘤相关巨噬细胞（TAMs）是髓系细胞的一个异质群体，它决定着肿瘤微环境（TME）的炎症基调。本研究揭示了清道夫受体 CD36 抑制 TAM 炎症状态的机制。CD36在TAMs中上调并与免疫抑制特征相关，髓系特异性删除CD36可显著降低肿瘤生长。此外，CD36缺失的TAM获得了炎症特征，包括I型干扰素（IFN-I）分泌升高，这反映了在癌症患者中观察到的CD36与IFN-I反应之间的反相关性。CD36缺陷TAMs产生的IFN-I，尤其是IFNβ，直接诱导肿瘤细胞静止并延缓肿瘤生长。从机理上讲，CD36 通过氧化脂质信号下游的 p38 激活，对巨噬细胞中的 IFN-I 信号起到天然抑制作用。这些发现确定了 CD36 是 TAM 功能和肿瘤炎症微环境的关键调节因子，为药物抑制 CD36 以恢复抗肿瘤免疫力提供了更多的依据。
{"title":"Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type-I IFN Signaling.","authors":"Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech","doi":"10.1158/0008-5472.CAN-23-4027","DOIUrl":"10.1158/0008-5472.CAN-23-4027","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) are a heterogeneous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment. In this study, we unveiled a mechanism by which scavenger receptor cluster of differentiation 36 (CD36) suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I IFN (IFNI) production, mirroring the inverse correlation between CD36 and IFNI response observed in patients with cancer. IFNI, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFNI signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacologic inhibition of CD36 to rejuvenate antitumor immunity. Significance: CD36 in tumor-associated macrophages mediates immunosuppression and can be targeted as a therapeutic avenue for stimulating interferon production and increasing the efficacy of immunotherapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"462-476"},"PeriodicalIF":12.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638412","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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