Cancer discovery最新文献

{"title":"MARK2/MARK3 kinases are catalytic co-dependencies 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":"<p><p>The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is 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 H. 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 co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a 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":"<p><p>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 over-expressed 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 induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed 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 HIF1a hypoxic response in PDAC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Bias: The Next Swing at IL2 Therapy.","authors":"Kayla R Kulhanek, Anusha Kalbasi","doi":"10.1158/2159-8290.CD-24-0558","DOIUrl":"10.1158/2159-8290.CD-24-0558","url":null,"abstract":"<p><p>Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells. See related article by Moynihan et al., p. 1206 (6). See related article by Kaptein et al., p. 1226 (7).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 7","pages":"1145-1146"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466378","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}

{"title":"Tumor Promoters and Opportunities for Molecular Cancer Prevention.","authors":"William Hill, Clare E Weeden, Charles Swanton","doi":"10.1158/2159-8290.CD-24-0128","DOIUrl":"10.1158/2159-8290.CD-24-0128","url":null,"abstract":"<p><p>Environmental carcinogens increase cancer incidence via both mutagenic and non-mutagenic mechanisms. There are over 500 known or suspected carcinogens classified by the International Agency for Research on Cancer. Sequencing of both cancerous and histologically non-cancerous tissue has been instrumental in improving our understanding of how environmental carcinogens cause cancer. Understanding how and defining which environmental or lifestyle exposures drive cancer will support cancer prevention. Recent research is revisiting the mechanisms of early tumorigenesis, paving the way for an era of molecular cancer prevention. Significance: Recent data have improved our understanding of how carcinogens cause cancer, which may reveal novel opportunities for molecular cancer prevention.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1154-1160"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316748","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}

{"title":"Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.","authors":"Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H S Wilms, Marcelo S da Silva, Robin A Jansen, Antonio Mulero-Sánchez, Elke Malzer, August Vidal, Cristina Santos, Ramón Salazar, Rosangela A M Wailemann, Thompson E P Torres, Giulia De Conti, Jonne A Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S Kovach, Hugo A Armelin, Hein Te Riele, Alexander van Oudenaarden, Haojie Jin, Roderick L Beijersbergen, Alberto Villanueva, Rene H Medema, Rene Bernards","doi":"10.1158/2159-8290.CD-23-0216","DOIUrl":"10.1158/2159-8290.CD-23-0216","url":null,"abstract":"<p><p>Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1276-1301"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292881","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}

{"title":"CD8-Targeted IL2 Unleashes Tumor-Specific Immunity in Human Cancer Tissue by Reviving the Dysfunctional T-cell Pool.","authors":"Paulien Kaptein, Nadine Slingerland, Christina Metoikidou, Felix Prinz, Simone Brokamp, Mercedes Machuca-Ostos, Guido de Roo, Ton N M Schumacher, Yik A Yeung, Kelly D Moynihan, Ivana M Djuretic, Daniela S Thommen","doi":"10.1158/2159-8290.CD-23-1263","DOIUrl":"10.1158/2159-8290.CD-23-1263","url":null,"abstract":"<p><p>Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune-checkpoint blockade can restore antitumor T-cell function in some patients; however, most do not respond to this therapy, often despite T-cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8-IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8-IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T-cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8-IL2 was able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for patients with cancer. Significance: Reinvigorating T cells is crucial for response to checkpoint blockade therapy. However, emerging evidence suggests that the PD-1/PD-L1 axis is not the sole impediment for activating T cells within tumors. Selectively targeting cytokines toward specific T-cell subsets might overcome these barriers and stimulate T cells within resistant tumors. See related article by Moynihan et al., p. 1206 (32).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1226-1251"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334811","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}

{"title":"Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.","authors":"Javier Carmona, Elena Chavarria, Kate Donoghue, Christina von Gertten, Petra Oberrauch, Emma Pailler, Giovanni Scoazec, Ruud Weijer, Judith Balmaña, Irene Brana, Cinzia Brunelli, Suzette Delaloge, Marc Deloger, Pierre Delpy, Ingemar Ernberg, Rebecca C Fitzgerald, Elena Garralda, Martin Lablans, Janne Lëhtio, Carlos Lopez, Maialen Fernández, Rosalba Miceli, Paolo Nuciforo, Raquel Perez-Lopez, Elena Provenzano, Marjanka K Schmidt, Cesar Serrano, Neeltje Steeghs, David Tamborero, Valtteri Wirta, Richard D Baird, Karen Barker, Fabrice Barlesi, Michael Baumann, Jonas Bergh, Filippo de Braud, Karim Fizazi, Stefan Fröhling, Alejandro Piris-Giménez, Kenneth Seamon, Michiel S Van der Heijden, Wilbert Zwart, Josep Tabernero","doi":"10.1158/2159-8290.CD-24-0377","DOIUrl":"10.1158/2159-8290.CD-24-0377","url":null,"abstract":"<p><p>Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1147-1153"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316747","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}

{"title":"Combining TIGIT Blockade with MDSC Inhibition Hinders Breast Cancer Bone Metastasis by Activating Antitumor Immunity.","authors":"Lea Monteran, Nour Ershaid, Ye'ela Scharff, Yazeed Zoabi, Tamer Sanalla, Yunfeng Ding, Anna Pavlovsky, Yael Zait, Marva Langer, Tal Caller, Anat Eldar-Boock, Camila Avivi, Amir Sonnenblick, Ronit Satchi-Fainaro, Iris Barshack, Noam Shomron, Xiang H-F Zhang, Neta Erez","doi":"10.1158/2159-8290.CD-23-0762","DOIUrl":"10.1158/2159-8290.CD-23-0762","url":null,"abstract":"<p><p>Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1β as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1β are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1β inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1252-1275"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012209","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}

{"title":"Expression of Concern: Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.","authors":"Aayoung Hong, Gatien Moriceau, Lu Sun, Shirley Lomeli, Marco Piva, Robert Damoiseaux, Sheri L Holmen, Norman E Sharpless, Willy Hugo, Roger S Lo","doi":"10.1158/2159-8290.CD-24-0612","DOIUrl":"10.1158/2159-8290.CD-24-0612","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 7","pages":"1356"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466375","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}

{"title":"Pan-RAF:MEK Molecular Glues Take Center Stage.","authors":"Matthew J Hangauer, Jorge Silvio Gutkind, Fleur M Ferguson","doi":"10.1158/2159-8290.CD-24-0539","DOIUrl":"10.1158/2159-8290.CD-24-0539","url":null,"abstract":"<p><p>In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway-driven tumors. See related article by Ryan et al., p. 1190 (1).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 7","pages":"1143-1144"},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466376","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}