Yibo Fan, Shlipa S. Dhar, Jiankang Khang, Xiaodan Yo, Ruiping Wang, A. Scott, Melissa Pool Pizzi, Lang Ma, S. Shao, M. S. Da Silva, Jingjing Wu, N. Shanbhag, Langhua Wang, M. Curran, Shumei Song, J. Ajani
Peritoneal metastasis (PC), the common sites of gastric adenocarcinoma (GAC) metastasis, remains resistant to therapies available in the clinics and new target is strived to be found. CD47 is one of the major players in conveying the “don’t eat me” signal upon binding its receptor SIRPα on myeloid cells which evade innate immune responses. Previously clinical studies on the blockade of CD47 alone resulted in limited clinical benefits suggesting that other target(s) must be inhibited simultaneously with CD47 for gaining advantage. Here, we found that CD47 was highly expressed on peritoneal malignant cells and its overexpression was a poor prognosticator. Additionally, we observed that Galectin-3 (Gal-3) was highly enriched in tumor cluster and was positively correlated with CD47 expression in short survival of patients revealed by scRNA-seq and metastatic GAC samples. Moreover, we found double positive of Gal-3 and CD47 significantly associated with diffuse type, poor differentiation, and tumor relapse. Mechanistically, Depletion of Gal-3 in mouse tumor and human tumor cells reduced the levels of CD47 through inhibition c-Myc expression and its binding to the promoter of CD47. Additionally, tumor-derived Gal-3 were found critical for tumor progression accompanied with protected GAC cells from phagocytosis by macrophages. Gal-3 deficiency resulted in a marked reduction in M2 macrophages and elevated T cell effector activity. Dual blockade of Gal-3 and CD47 significantly decreased tumor growth by promoted phagocytosis, repolarization of macrophage and boosted T cell immune responses in the tumor microenvironment. Our data uncover that Gal-3 synergizes with CD47 to suppress phagocytosis and orchestrates immunosuppressed milieu in the tumor microenvironment warrants combination therapeutic strategy in GAC patients with peritoneal metastases. Citation Format: Yibo Fan, Shumei Song, Yuan Li, Shilpa Dhar, Jiankang Jin, Xiaodao Yao, Ruiping Wang, Ailing Wang, Melissa Pool Pizzi, Jingjing Wu, Katsuhiro Yoshimura, Lang Ma, Samir Hanash, George Calin, Linghua Wang, Michael Curran, Jaffer Ajani. Galectin-3 synergizes with CD47 to suppress phagocytosis and T cell immunity in peritoneal metastases of gastric adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4433.
{"title":"Galectin-3 synergizes with CD47 to Suppress Phagocytosis and T cell immunity in Peritoneal Metastases of Gastric Adenocarcinoma","authors":"Yibo Fan, Shlipa S. Dhar, Jiankang Khang, Xiaodan Yo, Ruiping Wang, A. Scott, Melissa Pool Pizzi, Lang Ma, S. Shao, M. S. Da Silva, Jingjing Wu, N. Shanbhag, Langhua Wang, M. Curran, Shumei Song, J. Ajani","doi":"10.52519/00054","DOIUrl":"https://doi.org/10.52519/00054","url":null,"abstract":"\u0000 Peritoneal metastasis (PC), the common sites of gastric adenocarcinoma (GAC) metastasis, remains resistant to therapies available in the clinics and new target is strived to be found. CD47 is one of the major players in conveying the “don’t eat me” signal upon binding its receptor SIRPα on myeloid cells which evade innate immune responses. Previously clinical studies on the blockade of CD47 alone resulted in limited clinical benefits suggesting that other target(s) must be inhibited simultaneously with CD47 for gaining advantage. Here, we found that CD47 was highly expressed on peritoneal malignant cells and its overexpression was a poor prognosticator. Additionally, we observed that Galectin-3 (Gal-3) was highly enriched in tumor cluster and was positively correlated with CD47 expression in short survival of patients revealed by scRNA-seq and metastatic GAC samples. Moreover, we found double positive of Gal-3 and CD47 significantly associated with diffuse type, poor differentiation, and tumor relapse. Mechanistically, Depletion of Gal-3 in mouse tumor and human tumor cells reduced the levels of CD47 through inhibition c-Myc expression and its binding to the promoter of CD47. Additionally, tumor-derived Gal-3 were found critical for tumor progression accompanied with protected GAC cells from phagocytosis by macrophages. Gal-3 deficiency resulted in a marked reduction in M2 macrophages and elevated T cell effector activity. Dual blockade of Gal-3 and CD47 significantly decreased tumor growth by promoted phagocytosis, repolarization of macrophage and boosted T cell immune responses in the tumor microenvironment. Our data uncover that Gal-3 synergizes with CD47 to suppress phagocytosis and orchestrates immunosuppressed milieu in the tumor microenvironment warrants combination therapeutic strategy in GAC patients with peritoneal metastases.\u0000 Citation Format: Yibo Fan, Shumei Song, Yuan Li, Shilpa Dhar, Jiankang Jin, Xiaodao Yao, Ruiping Wang, Ailing Wang, Melissa Pool Pizzi, Jingjing Wu, Katsuhiro Yoshimura, Lang Ma, Samir Hanash, George Calin, Linghua Wang, Michael Curran, Jaffer Ajani. Galectin-3 synergizes with CD47 to suppress phagocytosis and T cell immunity in peritoneal metastases of gastric adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4433.","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"87 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116298497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziheng Chen, I. Ho, Liang Yan, Shujuan Chen, M. Soeung, Jonathan L. Rose, Sanjana Srinivasan, A. Viale, A. Carugo, G. Genovese, W. Yao, Ningping Feng, J. Gay, J. Marszalek, H. Ying, G. Draetta
Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monounsaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells. Citation Format: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta. Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1683.
{"title":"Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance","authors":"Ziheng Chen, I. Ho, Liang Yan, Shujuan Chen, M. Soeung, Jonathan L. Rose, Sanjana Srinivasan, A. Viale, A. Carugo, G. Genovese, W. Yao, Ningping Feng, J. Gay, J. Marszalek, H. Ying, G. Draetta","doi":"10.52519/00047","DOIUrl":"https://doi.org/10.52519/00047","url":null,"abstract":"\u0000 Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monounsaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells.\u0000 Citation Format: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta. Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1683.","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"116 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132852144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. Rubino, S. Schur, S. McGovern, C. Kamiya-Matsuoka, F. DeMonte, S. Raza
{"title":"Impact of Salvage Surgery and Re-irradiation for Radiation Failed Recurrent Skull Base Meningiomas","authors":"F. Rubino, S. Schur, S. McGovern, C. Kamiya-Matsuoka, F. DeMonte, S. Raza","doi":"10.52519/00079","DOIUrl":"https://doi.org/10.52519/00079","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131156935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Kunnimalaiyaan, A. Dadbin, Y. Henderson, Elena McBeath Fujiwara, C. Stephan, Roza Nurieca, N. Busaidy, J. Wang, Stephan Lai, M. Cabanillas, M. Zafereo, R. Dadu, M. Hofmann
{"title":"Therapeutic Potential of Ralimetinib, a p38/MAPK14 Inhibitor, in Anaplastic Thyroid Cancer","authors":"M. Kunnimalaiyaan, A. Dadbin, Y. Henderson, Elena McBeath Fujiwara, C. Stephan, Roza Nurieca, N. Busaidy, J. Wang, Stephan Lai, M. Cabanillas, M. Zafereo, R. Dadu, M. Hofmann","doi":"10.52519/00062","DOIUrl":"https://doi.org/10.52519/00062","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128294099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sonia A Patel, M. Nilsson, Yan Yang, Xaoxing Yu, Fahao Zhang, A. Poteete, Xiaoyang Ren, X. Le, Li Shen, Jing Wang, J. Heymach
{"title":"IL-6 contributes to the suppression of T and NK cell anti-tumor activity in EGFR-mutant NSCLC","authors":"Sonia A Patel, M. Nilsson, Yan Yang, Xaoxing Yu, Fahao Zhang, A. Poteete, Xiaoyang Ren, X. Le, Li Shen, Jing Wang, J. Heymach","doi":"10.52519/00073","DOIUrl":"https://doi.org/10.52519/00073","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130590583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mabel Perez-Oquendo, Roxsan Manshouri, Jared J. Fradette, D. Gibbons
{"title":"K811 acetylation regulates ZEB1 dimerization, protein stability, and NuRD complex interactions to promote lung adenocarcinoma progression and metastasis","authors":"Mabel Perez-Oquendo, Roxsan Manshouri, Jared J. Fradette, D. Gibbons","doi":"10.52519/00075","DOIUrl":"https://doi.org/10.52519/00075","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"126 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134126516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Loss of BRD7 promotes breast cancer lung metastasis by reprogramming the tumor immune microenvironment","authors":"J. Mondal, Junfeng Zhang, F. Giancotti, J. Huse","doi":"10.52519/00068","DOIUrl":"https://doi.org/10.52519/00068","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123182210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bingnan Zhang, Yan Yang, A. Stewart, Runsheng Wang, K. Ramkumar, R. Cardnell, Azusa Tanimoto, Ali Ibraham, K. Concannon, Ben Morris, L. Diao, Qi Wang, Jing Wang, C. Gay, J. Heymach, L. Byers
{"title":"Validating DLL3-targeting CAR T in small cell lung cancer","authors":"Bingnan Zhang, Yan Yang, A. Stewart, Runsheng Wang, K. Ramkumar, R. Cardnell, Azusa Tanimoto, Ali Ibraham, K. Concannon, Ben Morris, L. Diao, Qi Wang, Jing Wang, C. Gay, J. Heymach, L. Byers","doi":"10.52519/00099","DOIUrl":"https://doi.org/10.52519/00099","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"355 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134480784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hiroki Akiyama, R. Zhao, Yuki Nishida, Lauren B Ostermann, Poo Yee Mak, Edward Ayoub, Sujan Piya, B. Carter, M. Andreeff, J. Ishizawa
{"title":"Mitochondrial Respiration Regulates GPX4 Inhibition-Induced Ferroptosis in Acute Myeloid Leukemia","authors":"Hiroki Akiyama, R. Zhao, Yuki Nishida, Lauren B Ostermann, Poo Yee Mak, Edward Ayoub, Sujan Piya, B. Carter, M. Andreeff, J. Ishizawa","doi":"10.52519/00042","DOIUrl":"https://doi.org/10.52519/00042","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"74 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115998577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. L. Rodriguez, Limo Chen, Yanil Li, S. Miao, D. Peng, Jared Fradetta, L. Diao, J. Konen, A. Padhye, Laura Gibson, J. Ochieng, Xiaofei Zhou, Jing Wang, D. Gibbons
{"title":"Targeting immunosuppressive classical monocytes prevents immunotherapy resistance","authors":"B. L. Rodriguez, Limo Chen, Yanil Li, S. Miao, D. Peng, Jared Fradetta, L. Diao, J. Konen, A. Padhye, Laura Gibson, J. Ochieng, Xiaofei Zhou, Jing Wang, D. Gibbons","doi":"10.52519/00077","DOIUrl":"https://doi.org/10.52519/00077","url":null,"abstract":"","PeriodicalId":409973,"journal":{"name":"Leading Edge of Cancer Research Symposium: Poster Session","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124652520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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