Cancer discovery最新文献

{"title":"TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells.","authors":"Neibla Priego, Ana de Pablos-Aragoneses, María Perea-García, Valentina Pieri, Carolina Hernández-Oliver, Laura Álvaro-Espinosa, Andrea Rojas, Oliva Sánchez, Ariane Steindl, Eduardo Caleiras, Fernando García, Santiago García-Martín, Osvaldo Graña-Castro, Sandra García-Mulero, Diego Serrano, Paloma Velasco-Beltrán, Borja Jiménez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Rudà, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asís Palazón, Manuel Valiente","doi":"10.1158/2159-8290.CD-24-0134","DOIUrl":"10.1158/2159-8290.CD-24-0134","url":null,"abstract":"<p><p>Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here, we dissect the heterogeneity in metastasis-associated astrocytes using single-cell RNA sequencing and report a population that blocks the antitumoral activity of infiltrating T cells. This protumoral activity is mediated by the secretion of tissue inhibitor of metalloproteinase-1 (TIMP1) from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of tissue inhibitor of metalloproteinase-1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications. Significance: This study presents a significant advancement in understanding immune modulation in brain tumors and offers new insights into the potential therapeutic interventions for brain metastases. See related commentary by Lorger and James, p. 11.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"179-201"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361163","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 Neuroscience of Brain Tumors: From Multicellular Networks to Neuroscience-Instructed Cancer Therapies","authors":"Varun Venkataramani, Yvonne Yang, Sebastian Ille, Bogdana Suchorska, Sonja Loges, Heike Tost, Felix Sahm, Stefan M. Pfister, Andreas Trumpp, Sandro M. Krieg, Thomas Kuner, Wolfgang Wick, Frank Winkler","doi":"10.1158/2159-8290.cd-24-0194","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0194","url":null,"abstract":"Deepening our understanding of neuro-cancer interactions can innovate brain tumor treatment. This mini review unfolds the most relevant and recent insights into the neural mechanisms contributing to brain tumor initiation, progression, and resistance, including synaptic connections between neurons and cancer cells, paracrine neuro-cancer signaling, and cancer cells’ intrinsic neural properties. We explain the basic and clinical–translational relevance of these findings, identify unresolved questions and particularly interesting future research avenues, such as central nervous system neuro-immunooncology, and discuss the potential transferability to extracranial cancers. Lastly, we conceptualize ways toward clinical trials and develop a roadmap toward neuroscience-instructed brain tumor therapies. Significance: Neural influences on brain tumors drive their growth and invasion. Herein, we develop a roadmap to use these fundamentally new insights into brain tumor biology for improved outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"40 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968216","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":"Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal","authors":"Ángel Fernández-Sanromán, Annika Fendler, Benjy J.Y. Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed. Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T.C. Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J.S. Furness, Kate Young, David Nicol, Sarah Maria. Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic","doi":"10.1158/2159-8290.cd-24-0499","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0499","url":null,"abstract":"While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936175","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":"Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.","authors":"Ángel Fernández-Sanromán, Annika Fendler, Benjy J Y Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T C Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J S Furness, Kate Young, David Nicol, Sarah Maria Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic","doi":"10.1158/2159-8290.CD-24-0499","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0499","url":null,"abstract":"<p><p>While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945085","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":"Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution","authors":"Haoran Ma, Supriya Srivastava, Shamaine Wei Ting Ho, Chang Xu, Benedict Shi Xiang Lian, Xuewen Ong, Su Ting Tay, Taotao Sheng, Huey Yew Jeffrey Lum, Siti Aishah Binte Abdul Ghani, Yunqiang Chu, Kie Kyon Huang, Yeek Teck Goh, Minghui Lee, Takeshi Hagihara, Clara Shi Ya Ng, Angie Lay Keng Tan, Yanrong Zhang, Zichen Ding, Feng Zhu, Michelle Shu Wen Ng, Craig Ryan Cecil Joseph, Hui Chen, Zhen Li, Joseph J. Zhao, Sun Young Rha, Ming Teh, Joe Yeong, Wei Peng Yong, Jimmy Bok-Yan So, Raghav Sundar, Patrick Tan","doi":"10.1158/2159-8290.cd-24-0605","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0605","url":null,"abstract":"Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity. To explore geospatial interactions in tumor ecosystems, we integrated 2,138 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 226 GC samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers such as SOX9. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936174","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":"Effects of an initial anti-CD19 CAR T-cell therapy on subsequent anti-CD22 CAR T-cell manufacturing and clinical outcomes in patients with r/r LBCL","authors":"Yi-Jiun Su, Anne Marijn Kramer, Mark P. Hamilton, Neha Agarwal, Hrishikesh K. Srinagesh, John H. Baird, Bita Sahaf, Adam Kuo, Zachary J. Ehlinger, Moksha H. Desai, Skyler P. Rietberg, Ramya Tunuguntla, Shabnum Patel, Harshini Chinnasamy, Nikolaos Gkitsas-Long, Dorota D. Klysz, Annie Kathleen. Brown, Sushma Bharadwaj, Saurabh Dahiya, Melody Smith, Lori Muffly, Crystal L. Mackall, Zinaida Good, Steven A. Feldman, David B. Miklos, Matthew J. Frank","doi":"10.1158/2159-8290.cd-24-1071","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1071","url":null,"abstract":"Patients with large B-cell lymphoma (LBCL) progressing after anti-CD19 CAR T-cell (CAR19) therapy have poor outcomes. Subsequent CAR T-cell therapy shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 CAR19-refractory LBCL patients who received anti-CD22 CAR T-cell (CAR22) in a phase 1b trial (NCT04088890). Residual CAR19 was unquantifiable in 17 of 33 evaluable patients post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak CAR19 transgene levels did not affect CAR22 efficacy or toxicities. CAR22 products from patients undergoing leukapheresis &amp;gt; 6 months post-CAR19 had higher CD4+ naïve T and CD4+/CD8+ T- central memory (TCM) cells, with lower CD4+ T-effector memory cells. High and low percentages of CAR22 TCM and TEM, respectively, were correlated with CAR22 transduction efficiency and achieving complete response. Residual CAR19 and leukapheresis timing did not significantly affect outcomes, while CAR22 product composition was significantly correlated with treatment response.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"28 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936178","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":"Chronic viral mimicry induction following p53 loss promotes immune evasion","authors":"Charles A. Ishak, Sajid A. Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M. Gonzaga, Melanie Peralta, Ilinca M. Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N. Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E. Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S. Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran. Austin, Peter J.B. Sabatini, Benjamin D. Greenbaum, Catherine A. O'Brien, Trevor G. Shepherd, Ming Sound Tsao, Katherine B. Chiappinelli, Amit M. Oza, Blaise A. Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D. De Carvalho","doi":"10.1158/2159-8290.cd-24-0094","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0094","url":null,"abstract":"Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"35 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936209","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":"The Hallmarks of Predictive Oncology","authors":"Akshat Singhal, Xiaoyu Zhao, Patrick Wall, Emily So, Guido Calderini, Alexander Partin, Natasha Koussa, Priyanka Vasanthakumari, Oleksandr Narykov, Yitan Zhu, Sara E. Jones, Farnoosh Abbas-Aghababazadeh, Sisira Kadambat Nair, Jean-Christophe Bélisle-Pipon, Athmeya Jayaram, Barbara A. Parker, Kay T. Yeung, Jason I. Griffiths, Ryan Weil, Aritro Nath, Benjamin Haibe-Kains, Trey Ideker","doi":"10.1158/2159-8290.cd-24-0760","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0760","url":null,"abstract":"The rapid evolution of machine learning has led to a proliferation of sophisticated models for predicting therapeutic responses in cancer. While many of these show promise in research, standards for clinical evaluation and adoption are lacking. Here, we propose seven hallmarks by which predictive oncology models can be assessed and compared. These are Data Relevance and Actionability, Expressive Architecture, Standardized Benchmarking, Generalizability, Interpretability, Accessibility and Reproducibility, and Fairness. Considerations for each hallmark are discussed along with an example model scorecard. We encourage the broader community, including researchers, clinicians, and regulators, to engage in shaping these guidelines toward a concise set of standards. Significance: As the field of artificial intelligence evolves rapidly, these hallmarks are intended to capture fundamental, complementary concepts necessary for the progress and timely adoption of predictive modeling in precision oncology. Through these hallmarks, we hope to establish standards and guidelines that enable the symbiotic development of artificial intelligence and precision oncology.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"48 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929405","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":"Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants","authors":"Jinsuke Nishino, Wenhuo Hu, Ashwin Kishtagari, Bo Shen, Xiang Gao, Caroline M. Blackman, Adetola Kassim, Naimisha Marneni, Abhisar V. Cherukuri, Russell Vittrup, Fatma N. Kalkan, Rahul Shah, Chul Ahn, Ang Gao, Abeer Ahmedrabie, Robert H. Collins, Amer M. Zeidan, Aram Bidikian, Lohith Gowda, Brian C. Shaffer, Yazan F. Madanat, Zhiyu Zhao, Stephen S. Chung, Sean J. Morrison","doi":"10.1158/2159-8290.cd-24-0719","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0719","url":null,"abstract":"Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"41 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904831","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":"Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.","authors":"Tanjina Kader, Jia-Ren Lin, Clemens B Hug, Shannon Coy, Yu-An Chen, Ino de Bruijn, Natalie Shih, Euihye Jung, Roxanne J Pelletier, Mariana Lopez Leon, Gabriel Mingo, Dalia K Omran, Jong Suk Lee, Clarence Yapp, Baby A Satravada, Ritika Kundra, Yilin Xu, Sabrina Chan, Juliann B Tefft, Jeremy L Muhlich, Sarah H Kim, Stefan M Gysler, Judith Agudo, James R Heath, Nikolaus Schultz, Charles W Drescher, Peter K Sorger, Ronny Drapkin, Sandro Santagata","doi":"10.1158/2159-8290.CD-24-1366","DOIUrl":"10.1158/2159-8290.CD-24-1366","url":null,"abstract":"<p><p>High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863423","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}