Cancer discoveryPub Date : 2025-02-07DOI: 10.1158/2159-8290.CD-24-1662
Jack J Brzezinski, David Malkin
{"title":"Knudson's \"Two-Hit\" Hypothesis and Cancer Predisposition: A Bit More Complicated but Still Going Strong.","authors":"Jack J Brzezinski, David Malkin","doi":"10.1158/2159-8290.CD-24-1662","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1662","url":null,"abstract":"<p><p>This study by Treger and colleagues is a comprehensive evaluation of the genome and epigenome of tumors and constitutional tissue from children with Wilms tumor predisposition syndromes that demonstrates that the molecular features of Wilms tumors are dependent on the constitutional milieu of the patient in which they develop. See related article by Treger et al., p. 286.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"258-260"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363595","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}
Cancer discoveryPub Date : 2025-02-07DOI: 10.1158/2159-8290.cd-24-1317
Eunae You, Bidish K. Patel, Alexandra S. Rojas, Siyu Sun, Patrick Danaher, Natalie I. Ho, Ildiko E. Phillips, Michael J. Raabe, Yuhui Song, Katherine H. Xu, Joshua R. Kocher, Peter M. Richieri, Phoebe Shin, Martin S. Taylor, Linda T. Nieman, Benjamin D. Greenbaum, David T. Ting
{"title":"LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma","authors":"Eunae You, Bidish K. Patel, Alexandra S. Rojas, Siyu Sun, Patrick Danaher, Natalie I. Ho, Ildiko E. Phillips, Michael J. Raabe, Yuhui Song, Katherine H. Xu, Joshua R. Kocher, Peter M. Richieri, Phoebe Shin, Martin S. Taylor, Linda T. Nieman, Benjamin D. Greenbaum, David T. Ting","doi":"10.1158/2159-8290.cd-24-1317","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1317","url":null,"abstract":"Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that require mechanisms to manage this repeat “viral” load and attenuate innate immune responses. Here, we show that the LINE-1 ORF1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor (PRR)-mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the dsRNA sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of PRRs demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies (PBs) with the dsRNA helicase MOV10 were found important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human PDAC patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"47 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367368","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}
Cancer discoveryPub Date : 2025-02-07DOI: 10.1158/2159-8290.CD-24-0187
Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska
{"title":"Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma.","authors":"Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska","doi":"10.1158/2159-8290.CD-24-0187","DOIUrl":"10.1158/2159-8290.CD-24-0187","url":null,"abstract":"<p><strong>Significance: </strong>The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"401-426"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543875","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}
Cancer discoveryPub Date : 2025-02-07DOI: 10.1158/2159-8290.CD-23-1336
Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suvà
{"title":"Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer.","authors":"Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suvà","doi":"10.1158/2159-8290.CD-23-1336","DOIUrl":"10.1158/2159-8290.CD-23-1336","url":null,"abstract":"<p><p>Glioblastoma (GBM) is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. In this study, we model this ecosystem by growing GBM into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA sequencing analysis suggests that, compared with matched gliomasphere models, GBM cortical organoids more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of GBM transcripts and GFP to nonmalignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased toward defined GBM cell states and astroglia cell types. These results extend previous GBM organoid modeling efforts and suggest widespread intercellular transfer in the GBM neuroglial microenvironment. Significance: Models that recapitulate intercellular communications in GBM are limited. In this study, we leverage GBM cortical organoids to characterize widespread mRNA and GFP transfer from malignant to nonmalignant cells in the GBM neuroglial microenvironment. This transfer involves extracellular vesicles, may contribute to reprogramming the microenvironment, and may extend to other cancer types. See related commentary by Shakya et al., p. 261.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"299-315"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380088","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}
Cancer discoveryPub Date : 2025-02-07DOI: 10.1158/2159-8290.CD-24-1661
Sajina Shakya, Christopher G Hubert, Justin D Lathia
{"title":"A Material Transfer Agreement between Glioblastoma and Normal Brain Cells.","authors":"Sajina Shakya, Christopher G Hubert, Justin D Lathia","doi":"10.1158/2159-8290.CD-24-1661","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1661","url":null,"abstract":"<p><p>Tumor cells communicate with normal cells in various ways, typically leading to the exploitation of resources of the normal cells by tumor cells for their benefit. In this issue, Mangena and colleagues use three-dimensional organoid models to show the transfer of GFP and mRNA from malignant glioblastoma to nonmalignant cells in cerebral organoid models; this transfer is facilitated by extracellular vesicles and possibly tunneling nanotubes, demonstrating how nonmalignant cells in the tumor microenvironment can be exploited by neighboring malignant cells. See related article by Mangena et al., p. 299.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"261-263"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363580","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}
Cancer discoveryPub Date : 2025-02-06DOI: 10.1158/2159-8290.CD-24-1509
Marina N Sharifi, Jamie M Sperger, Amy K Taylor, Katharine E Tippins, Shannon R Reese, Viridiana Carreno, Katherine R Kaufmann, Alex H Chang, Luke A Nunamaker, Charlotte Linebarger, Leilani Mora-Rodriguez, Jennifer L Schehr, Hannah M Krause, Kyle T Helzer, Matthew L Bootsma, Grace C Blitzer, John M Floberg, Christos E Kyriakopoulos, Hamid Emamekhoo, Elisabeth I Heath, Meghan Wells, Scott T Tagawa, Martin Sjöström, Atish D Choudhury, Menggang Yu, Andrew J Armstrong, Dana E Rathkopf, Himisha Beltran, Peter S Nelson, Felix Y Feng, Scott M Dehm, David Kosoff, Xiao X Wei, Rana R McKay, Shuang G Zhao, Joshua M Lang
{"title":"High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.","authors":"Marina N Sharifi, Jamie M Sperger, Amy K Taylor, Katharine E Tippins, Shannon R Reese, Viridiana Carreno, Katherine R Kaufmann, Alex H Chang, Luke A Nunamaker, Charlotte Linebarger, Leilani Mora-Rodriguez, Jennifer L Schehr, Hannah M Krause, Kyle T Helzer, Matthew L Bootsma, Grace C Blitzer, John M Floberg, Christos E Kyriakopoulos, Hamid Emamekhoo, Elisabeth I Heath, Meghan Wells, Scott T Tagawa, Martin Sjöström, Atish D Choudhury, Menggang Yu, Andrew J Armstrong, Dana E Rathkopf, Himisha Beltran, Peter S Nelson, Felix Y Feng, Scott M Dehm, David Kosoff, Xiao X Wei, Rana R McKay, Shuang G Zhao, Joshua M Lang","doi":"10.1158/2159-8290.CD-24-1509","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1509","url":null,"abstract":"<p><p>The development of treatment resistance remains universal for patients with metastatic prostate cancer, driven by AR alterations and lineage state transitions. Identifying the evolution of lineage transitions in treatment resistance has been limited by the challenges of collecting serial tissue biopsies on treatment, which can be overcome using blood-based liquid biopsies. Utilizing a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. 146 samples from 70 patients had tumor purity comparable to tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype defined by persistent AR signaling and high proliferation, as well as those with a neuroendocrine CTC phenotype, had significantly shorter survival than patients with luminal-A-like and low proliferation phenotypes. In a prospective substudy, pre-treatment CTC luminal-B-like phenotype was associated with early progression on 177Lu-PSMA-617.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254644","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}
Cancer discoveryPub Date : 2025-01-24DOI: 10.1158/2159-8290.cd-24-1368
Ilana Struys, Carolina Velázquez, Joske Ubels, Charlotte L. LeJeune, Markus J. van Roosmalen, Axel K.M. Rosendahl Huber, Anais J.C.N. van Leeuwen, Wouter Bossuyt, Bernard Thienpont, Thierry Voet, Kristel Van Calsteren, Liesbeth Lenaerts, Ruben van Boxtel, Frédéric Amant
{"title":"Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells","authors":"Ilana Struys, Carolina Velázquez, Joske Ubels, Charlotte L. LeJeune, Markus J. van Roosmalen, Axel K.M. Rosendahl Huber, Anais J.C.N. van Leeuwen, Wouter Bossuyt, Bernard Thienpont, Thierry Voet, Kristel Van Calsteren, Liesbeth Lenaerts, Ruben van Boxtel, Frédéric Amant","doi":"10.1158/2159-8290.cd-24-1368","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1368","url":null,"abstract":"Chemotherapy is included in the standard of care for cancer treatment during pregnancy. However, whether prenatal exposure to maternal chemotherapy treatment has a mutagenic impact on the fetal genome, remains unexplored. Therefore, we investigated mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) from neonates born to pregnant cancer patients treated with chemotherapy, as well as healthy pregnant women and untreated pregnant cancer patients. The mutational burden in HSPCs from neonates born to untreated pregnant cancer patients and to healthy controls was similar, but increased after prenatal exposure to varying types of chemotherapy regimens. Mutational signature analyses attributed the excess mutations to clock-like processes, which are active during normal cellular aging, or to direct mutagenesis by platinum-based drugs in neonates prenatally exposed to platinum-containing regimens. Our findings in the neonatal hematopoietic compartment are consistent with mutational signatures previously identified in cells of cancer survivors directly exposed to these chemotherapeutic drugs.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"76 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027222","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}
Cancer discoveryPub Date : 2025-01-21DOI: 10.1158/2159-8290.cd-23-0543
Rahat Alam,Anna Reva,David G Edwards,Bree M Lege,Laura S Munoz-Arcos,Carolina Reduzzi,Swarnima Singh,Xiaoxin Hao,Yi-Hsuan Wu,Zeru Tian,Laura M Natalee,Gargi Damle,Deniz Demircioglu,Yixian Wang,Ling Wu,Elisabetta Molteni,Dan Hasson,Bora Lim,Zbigniew Gugala,Jerry E Chipuk,Julie E Lang,Joseph A Sparano,Chonghui Cheng,Massimo Cristofanilli,Han Xiao,Xiang H-F Zhang,Igor L Bado
{"title":"Bone-Induced Her2 Promotes Secondary Metastasis in HR+/Her2- Breast Cancer.","authors":"Rahat Alam,Anna Reva,David G Edwards,Bree M Lege,Laura S Munoz-Arcos,Carolina Reduzzi,Swarnima Singh,Xiaoxin Hao,Yi-Hsuan Wu,Zeru Tian,Laura M Natalee,Gargi Damle,Deniz Demircioglu,Yixian Wang,Ling Wu,Elisabetta Molteni,Dan Hasson,Bora Lim,Zbigniew Gugala,Jerry E Chipuk,Julie E Lang,Joseph A Sparano,Chonghui Cheng,Massimo Cristofanilli,Han Xiao,Xiang H-F Zhang,Igor L Bado","doi":"10.1158/2159-8290.cd-23-0543","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-0543","url":null,"abstract":"Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 therapy. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2E CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"32 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991647","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}
Cancer discoveryPub Date : 2025-01-17DOI: 10.1158/2159-8290.cd-24-0442
Anagh A. Sahasrabuddhe, Xiaofei Chen, Kaiyu Ma, Rui Wu, Huan-Chang Liang, Richa Kapoor, Rishi R. Chhipa, Ozlem Onder, Courtney McFetridge, John S. Van Arnam, Xiao Zhang, Jennifer J.D. Morrissette, Vinodh Pillai, Marilyn M. Li, Philippe Szankasi, Venkatesha Basrur, Kevin P. Conlon, Tobias D. Raabe, Nathanael G. Bailey, Cory M. Hogaboam, Robert Rottapel, Junhyong Kim, Cristina López, Matthias Schlesner, Reiner Siebert, Kostiantyn Dreval, Ryan D. Morin, Loredana Moro, Michele Pagano, Louis M. Staudt, Megan S. Lim, Kojo S.J. Elenitoba-Johnson
{"title":"The FBXO45-GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis","authors":"Anagh A. Sahasrabuddhe, Xiaofei Chen, Kaiyu Ma, Rui Wu, Huan-Chang Liang, Richa Kapoor, Rishi R. Chhipa, Ozlem Onder, Courtney McFetridge, John S. Van Arnam, Xiao Zhang, Jennifer J.D. Morrissette, Vinodh Pillai, Marilyn M. Li, Philippe Szankasi, Venkatesha Basrur, Kevin P. Conlon, Tobias D. Raabe, Nathanael G. Bailey, Cory M. Hogaboam, Robert Rottapel, Junhyong Kim, Cristina López, Matthias Schlesner, Reiner Siebert, Kostiantyn Dreval, Ryan D. Morin, Loredana Moro, Michele Pagano, Louis M. Staudt, Megan S. Lim, Kojo S.J. Elenitoba-Johnson","doi":"10.1158/2159-8290.cd-24-0442","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0442","url":null,"abstract":"The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B cell (DLBCL) and follicular lymphoma (FL) is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B-cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mechanistically, FBXO45 targets the RHO guanine exchange factor ARHGEF2/GEF-H1 for ubiquitin-mediated degradation. Double genetic ablation of Fbxo45 and Arhgef2 ameliorated lymphoma formation. Transgenic knock-in mice harboring a GEF-H1 mutant unable to bind FBXO45 develop B-cell lymphomas with ~50% penetrance. Genome sequencing in human lymphomas identified mutually-exclusive FBXO45 copy number losses and ARHGEF2 gains, with combined frequencies ranging from 26.32% in FL to 45.12% in DLBCL. Notably, FBXO45 silencing enhances sensitivity to MEK1/2 inhibition. These results identify FBXO45 and ARHGEF2 as a novel tumor-suppressor and oncogene pair involved in the pathogenesis of B-cell lymphomas with significant implications for targeted therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988897","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":"PIN1 prolyl isomerase promotes initiation and progression of bladder cancer through the SREBP2-mediated cholesterol biosynthesis pathway","authors":"Xue Wang, Derrick Lee, Haibo Xu, Yuan Sui, Jill Meisenhelder, Tony Hunter","doi":"10.1158/2159-8290.cd-24-0866","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0866","url":null,"abstract":"Identities of functional pSer/Thr.Pro protein substrates of the PIN1 prolyl isomerase and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we found that PIN1 positively regulated bladder cancer cell proliferation, cell motility and urothelium clearance capacity in vitro and controlled tumor growth and potential metastasis in vivo. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways and a decrease in free/total cholesterol levels in PIN1-knockout bladder cancer cells. Moreover, we showed that PIN1 interacted with SREBP2 following its phosphorylation by the JNK MAP kinase at Ser455, which lies near the Site-2 cleavage site that generates the active, nuclear-form of SREBP2. Therapeutically, a combination of the sulfopin PIN1 covalent inhibitor and the simvastatin HMGCoA reductase inhibitor suppressed cell proliferation in vitro and tumor growth in vivo synergistically. Together, these findings emphasize that PIN1 can act as a driver and potential therapeutic target in bladder cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"60 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974775","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
