Cancer discovery最新文献_第8页

A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention. 一种可靶向分泌的神经蛋白驱动胰腺癌转移定植和 HIF1a 核保留。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-23-1323

Norihiro Yamaguchi, Y Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C Lorenz, Christine A Iacobuzio-Donahue, Sohail F Tavazoie

{"title":"A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.","authors":"Norihiro Yamaguchi, Y Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C Lorenz, Christine A Iacobuzio-Donahue, Sohail F Tavazoie","doi":"10.1158/2159-8290.CD-23-1323","DOIUrl":"10.1158/2159-8290.CD-23-1323","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2489-2508"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726945","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}

引用次数: 0

Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers. 表观遗传抑制剂和致癌抑制剂共同推动分化，杀死 KRAS 突变的结直肠癌。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-23-0866

Patrick Loi, Amy E Schade, Carrie L Rodriguez, Anjana Krishnan, Naiara Perurena, Van T M Nguyen, Yilin Xu, Marina Watanabe, Rachel A Davis, Alycia Gardner, Natalie F Pilla, Kaia Mattioli, Olesja Popow, Nuray Gunduz, Tamsin R M Lannagan, Samantha Fitzgerald, Ewa T Sicinska, Jia-Ren Lin, William Tan, Lauren K Brais, Kevin M Haigis, Marios Giannakis, Kimmie Ng, Sandro Santagata, Kristian Helin, Owen J Sansom, Karen Cichowski

引用次数: 0

MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer. 在人类癌症中，MARK2/MARK3 激酶是 YAP/TAZ 的催化共依赖因子。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-23-1529

Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc

{"title":"MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer.","authors":"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc","doi":"10.1158/2159-8290.CD-23-1529","DOIUrl":"10.1158/2159-8290.CD-23-1529","url":null,"abstract":"The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from Helicobacter pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression. Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas. See related commentary by Gauthier-Coles and Sheltzer, p. 2312.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2471-2488"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757214","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}

引用次数: 0

Correction: St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors. 更正：St. Jude幸存者门户：共享和分析儿童癌症幸存者的大型临床和基因组数据集。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-24-1432

Gavriel Y Matt, Edgar Sioson, Kyla Shelton, Jian Wang, Congyu Lu, Airen Zaldivar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Qi Liu, Stephanie R Sandor, Clay McLeod, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Yadav Sapkota, Carmen L Wilson, Nickhill Bhakta, Kirsten K Ness, Gregory T Armstrong, Melissa M Hudson, Leslie L Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou

引用次数: 0

RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis. 在 TET2 突变的克隆造血过程中，需要 P65 的 RNA 屏蔽来增强致癌炎症。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-24-0093

Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C Ferrall-Fairbanks, Jenna Fernandez, Terra L Lasho, Christy M Finke, Mohammed L Ibrahim, Kathy L McGraw, Michael Wysota, Amy L Aldrich, Christopher B Ryder, Christopher T Letson, Joshua Traina, Amy F McLemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A Sallman, Amer A Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M Patnaik, Eric Padron

引用次数: 0

Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells. 耐化疗高危神经母细胞瘤持久细胞的鉴定和特征描述。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-24-0046

Liron D Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J Wolpaw, Kevin Louault, Yael Goldstein, Lea F Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M Kendsersky, Jarrett M Lindsay, Colleen E Casey, Kateryna Krytska, Laura Scolaro, Matthew Tsang, David Groff, Smita Matkar, Josh R Kalna, Emily Mycek, Jayne McDevitt, Erin Runbeck, Tasleema Patel, Kathrin M Bernt, Shahab Asgharzadeh, Yves A DeClerck, Yael P Mossé, Kai Tan, John M Maris

{"title":"Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells.","authors":"Liron D Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J Wolpaw, Kevin Louault, Yael Goldstein, Lea F Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M Kendsersky, Jarrett M Lindsay, Colleen E Casey, Kateryna Krytska, Laura Scolaro, Matthew Tsang, David Groff, Smita Matkar, Josh R Kalna, Emily Mycek, Jayne McDevitt, Erin Runbeck, Tasleema Patel, Kathrin M Bernt, Shahab Asgharzadeh, Yves A DeClerck, Yael P Mossé, Kai Tan, John M Maris","doi":"10.1158/2159-8290.CD-24-0046","DOIUrl":"10.1158/2159-8290.CD-24-0046","url":null,"abstract":"Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. In this study, we used single-nucleus RNA sequencing and bulk whole-genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape, including suppression of MYC(N) activity and activation of NFκB signaling, and the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse. Significance: Approximately 50% of patients with high-risk neuroblastoma die of relapsed refractory disease. We identified the malignant cells that likely contribute to relapse and discovered key signaling pathways that mediate cellular persistence. Inhibition of these pathways and their downstream effectors is postulated to eliminate persister cells and prevent relapse. See related commentary by Wolf et al., p. 2308.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2387-2406"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859121","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}

引用次数: 0

Cancer in 2024. 巨蟹座：2024年

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-24-1451

引用次数: 0

Reflections on Advances in Cancer Research in 2024. 2024年癌症研究进展反思。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-24-1483

Katherine M Aird, Aadel A Chaudhuri, Jennifer L Guerriero, Shiri Gur-Cohen, Benjamin Izar, Brittany D Jenkins, Delphine Merino, Alejo E Rodriguez-Fraticelli, Shensi Shen, Itai Yanai

引用次数: 0

Characterization of Persister Cells Provides Insights into Mechanisms of Therapy Resistance in Neuroblastoma 持久性细胞的特性为神经母细胞瘤的耐药机制提供了新的见解

IF 28.2 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.cd-24-1357

Amber B. Wolf, C. Patrick Reynolds, Eveline Barbieri

引用次数: 0

Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells. 在人类非整倍体细胞中，需要增加 RNA 和蛋白质降解来抵消转录负担和蛋白毒性压力。

IF 29.7 1区医学

Cancer discovery Pub Date : 2024-12-02 DOI: 10.1158/2159-8290.CD-23-0309

Marica Rosaria Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Viganò, Giuseppina De Feudis, Eldad D Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mülleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Stefano Santaguida, Uri Ben-David

{"title":"Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells.","authors":"Marica Rosaria Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Viganò, Giuseppina De Feudis, Eldad D Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mülleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Stefano Santaguida, Uri Ben-David","doi":"10.1158/2159-8290.CD-23-0309","DOIUrl":"10.1158/2159-8290.CD-23-0309","url":null,"abstract":"Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. In this study, we dissected multiple diploid versus aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of patients with multiple myeloma to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically actionable vulnerabilities in aneuploid cells. Significance: Aneuploidy is a hallmark of cancer that is associated with poor prognosis and worse drug response. We reveal that cells with extra chromosomes compensate for their imbalanced DNA content by altering their RNA and protein metabolism, rendering them more sensitive to perturbation of RNA and protein degradation. See related commentary by Bakhoum, p. 2315.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2532-2553"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153171","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}

引用次数: 0