Cancer research最新文献

{"title":"Abstract CT002: Circulating tumor DNA status to direct adjuvant immunotherapy for mismatch repair deficient tumors","authors":"Yelena Yuriy Janjigian, Michael B. Foote, Melissa Lumish, Marinela Capanu, Joanne Chou, Julio Garcia-Aguilar, Martin Weiser, Jason Konner, Vivian Strong, Elizabeth Jewell, Jennifer Mueller, Steven Maron, Ping Gu, Rona Yaeger, Sree Chalasani, Andrea Cercek, Jia Li, Maliha Nusrat, Ryan Sugarman, David Jones, Daniela Molena, David Solit, Brian Loomis, Marc Ladanyi, Michael Berger, Luis A. Diaz","doi":"10.1158/1538-7445.am2025-ct002","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct002","url":null,"abstract":"Background: Patients with early-stage solid tumors who harbor minimal residual disease (MRD) following surgical resection as detected by circulating tumor DNA (ctDNA), have a high risk of recurrence. It remains uncertain whether therapeutic intervention of MRD in this context reduces cancer recurrence. We evaluated the efficacy of PD-1 blockade in resected early-stage mismatch repair deficient (MMRd) tumors with ctDNA-detected MRD, given high sensitivity of MMRd tumors to immune checkpoint blockade. Methods: We conducted a prospective clinical study assessing PD-1 blockade with pembrolizumab in patients with resected MMRd solid tumors treated with surgery and standard of care adjuvant therapy. Treatment with PD-1 blockade was guided by ctDNA status, measured 6-10 weeks after curative intent surgery and standard of care adjuvant therapy. Study arms included, Arm A (Interventional) comprised of ctDNA-positive patients treated with pembrolizumab for 6 months, and Arm B (Observational) comprised of ctDNA-negative patients. The primary endpoint was ctDNA clearance at 6 months in 40% of study patients. Recurrence-free survival (RFS) and overall survival (OS) were included as exploratory endpoints. Results: Three-hundred and three patients with resected MMRd solid tumors were screened and ctDNA status was measured in 174 of these patients in 16 different tumor types. Twenty-two patients (12.6%) were ctDNA positive and enrolled in Arm A (Interventional). Of these 22, 13 ctDNA-positive patients received six months of PD-1 blockade and 9 did not because of radiographically detected disease recurrence prior to initiation of therapy. Fifty-two ctDNA-negative patients were enrolled in Arm B (Observational) and observed. The median follow-up time for all patients was 32.1 months. The study met the primary endpoint; 85% (11/13) of patients in Arm A (Interventional) achieved ctDNA clearance at 6 months, the median RFS was not reached, and the recurrence rate was 38% (5/13). In those that were ctDNA positive that did not receive PD-1 blockade the median RFS was 0.8 months (95% CI 0.3-1.3) and the recurrence rate was 100% (9/9). In Arm B (Observational) the median RFS was not reached, and the recurrence rate was 5.9% (9/152). Overall survival at 2 years was 92% (95%CI: 79-100%) in ctDNA positive patients who received PD-1 blockade and 78% (95%CI: 55%-100%) in patients that did not receive PD-1 blockade. In ctDNA negative patients, the OS at 2 years was 98% (95%CI: 96%-100% ). Conclusion: Adjuvant PD-1 blockade directed by ctDNA status post-resection early-stage MMRd malignancies may provide clinical benefit in a agnostic of tumor type. Citation Format: Yelena Yuriy Janjigian, Michael B. Foote, Melissa Lumish, Marinela Capanu, Joanne Chou, Julio Garcia-Aguilar, Martin Weiser, Jason Konner, Vivian Strong, Elizabeth Jewell, Jennifer Mueller, Steven Maron, Ping Gu, Rona Yaeger, Sree Chalasani, Andrea Cercek, Jia Li, Maliha Nusrat, Ryan Sugarman, David Jones, Daniela M","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122996","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":"Abstract 6372: Combined tissue and liquid biopsy improves outcomes in advanced solid tumors: an exploratory analysis of the ROME trial","authors":"Paolo Marchetti, Simone Scagnoli, Edoardo Crimini, Simona Pisegna, Sofia Verkhovskaia, Giuseppe Curigliano, Sara Lonardi, Valentina Guarneri, Chiara Cremolini, Umberto Malapelle, Ettore D. Capoluongo, Paolo A. Ascierto, Fabio Puglisi, Giancarlo Pruneri, Giulia D'Amati, Bruna Cerbelli, Mauro Biffoni, Giuseppe Tonini, Lucia Del Mastro, Andrea Botticelli","doi":"10.1158/1538-7445.am2025-6372","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-6372","url":null,"abstract":"Background: The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Centralized next-generation sequencing (NGS) was performed on both tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx. A centralized Molecular Tumor Board (MTB) reviewed results to identify actionable alterations, with 400 patients subsequently randomized to tailored therapy (TT) or standard-of-care (SoC). In this trial, TT improved objective response rate (ORR) and progression-free survival (PFS) in the Intention to Treat population (ITT) Methods: This exploratory analysis evaluated the concordance between tissue (T) and liquid (L) biopsy results in detecting actionable alterations in ITT population. Concordance was defined as the detection of the same significant alterations in both biopsy types; discordance indicated detection in only one. Survival outcomes (OS and PFS) were analyzed across concordance groups. Due to the exploratory nature of the analysis, statistical significance was not determined Results: Concordance between tissue (T) and liquid (L) biopsies was 49%, with actionable alterations detected exclusively in tissue biopsies in 35% of patients and exclusively in liquid biopsies in 16%. Of the 203 discordant cases, 21% were attributed to test failures, 35% to discordant high tumor mutational burden (hTMB) detection, 1% to microsatellite instability (MSI) discrepancies, and 43.3% to differences in the detection of molecular alterations. The PI3K/PTEN/AKT/mTOR and ERBB2 pathways showed the highest discordance rates. Test results guided therapeutic choices in 84% and 65% of cases for tissue biopsy and liquid biopsy, respectively. Patients in the concordant T+L group receiving tailored therapy (TT) experienced significantly improved survival outcomes. Median overall survival (OS) was 11.05 vs. 7.70 months in the standard-of-care (SoC) group (HR 0.74; 95% CI: 0.51-1.07), and median progression-free survival (PFS) was 4.93 vs. 2.80 months (HR 0.55; 95% CI: 0.40-0.76). In contrast, the survival benefit of TT was less pronounced or absent in patients with discordant results. Overall, OS was higher in the T+L group (11.05 months), followed by the tissue-only group (9.93 months), and the liquid-only group (4.05 months). PFS followed a similar pattern, with the longest PFS observed in the T+L group (4.93 months) compared to 3.06 months in the tissue-only group and 2.07 months in the liquid-only group. Conclusions: Although the concordance rate between tissue and liquid biopsies was only 49%, the substantial increase in detection of actionable alterations (over 60% with the addition of liquid biopsy) and significative improvement of survival outcomes observed with combined T+L concordance strongly emphasize the importance of integrating both biopsy modalities to enhance precision oncology approaches. Citation Format: Paolo Marchetti, Simone Scagnoli, Edoardo Crimini, Simona Pisegna, Sofia Verkhovskaia, Gius","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122999","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":"Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.","authors":"Stephen L DeAngelo,Liang Zhao,Sofia Dziechciarz,Myungsun Shin,Sumeet Solanki,Andrii Balia,Marwa O El-Derany,Cristina Castillo,Yao Qin,Nupur K Das,Hannah N Bell,Joao A Paulo,Yuezhong Zhang,Nicholas J Rossiter,Elizabeth C McCulla,Jianping He,Indrani Talukder,Billy Wai-Lung Ng,Zachary T Schafer,Nouri Neamati,Joseph D Mancias,Markos Koutmos,Yatrik M Shah","doi":"10.1158/0008-5472.can-24-3478","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3478","url":null,"abstract":"Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer (CRC) cells feature elevated intracellular iron and reactive oxygen species (ROS) that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 ([1S,3R]-RSL3) is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides utilizing glutathione. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPX4, combined with inducible genetic knockdowns of GPX4 in CRC cell lines, we revealed here that GPX4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPX4 as the primary target of (S)-RSL3. Affinity pull-down mass spectrometry with modified (S)-RSL3 probes identified multiple selenoprotein targets, indicating broad selenoprotein inhibition. Further investigation of the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC showed that the selenoprotein inhibitor auranofin, an FDA-approved gold-salt, chemically induced oxidative cell death and ferroptosis in CRC models in vitro and in vivo. Similarly, genetic perturbation of ALKBH8, a tRNA-selenocysteine methyltransferase required for selenoprotein translation, suppressed CRC growth. In summary, these findings recharacterize the mechanism of (S)-RSL3 beyond GPX4 inhibition and establish selenoproteome disruption as a CRC therapeutic strategy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"131 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103674","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":"Reactivating cGAS-STING Signaling by Targeting SOS1 Enhances Antitumor Immunity in NRAS-Mutant Tumors.","authors":"Jia-Lu Shan,Kai-Ming Zhang,Wen-Qing Zhong,Xiao-Yu Yang,Zhi-Ling Li,Yun Huang,Tian Du,Dong Yang,Jia-Hong Tang,Yu-Hong Chen,Hai-Liang Zhang,Xiao-Feng Zhu,Rong Deng","doi":"10.1158/0008-5472.can-24-2983","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2983","url":null,"abstract":"NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type tumors, current therapies for NRAS-mutant cancers are limited. Here, analysis of RNA-sequencing data revealed a downregulation of the type I interferon response in NRAS-mutant tumors compared with NRAS wild-type tumors, which was associated with poor prognosis in NRAS-mutant melanoma. Knockdown of mutant NRAS, but not wild-type NRAS, enhanced the activation of cGAS-STING signaling. The formation of a trimeric complex between TBK1, STING, and IRF3, which is required for the activation and nuclear translocation, was blocked in NRAS-mutant tumor cells. Inactivation of innate immune signaling by mutant NRAS altered cytokine production, resulting in cell autonomous and non-cell autonomous signaling to prevent tumor cell death and in evasion of tumor immune surveillance. Screening of drugs for the ability to stimulate the release of CXCL10 revealed that SOS1 inhibitors reactivated cGAS-STING signaling in NRAS-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS-STING signaling and elicited an increased antitumor immune response in vitro and in vivo. Overall, this study provides insights into the regulation of anti-tumor immunity by mutant NRAS and uncovers a potential strategy for treating NRAS-mutant cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103735","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":"Adaptation to Volumetric Compression Drives an Apoptosis-Resistant and Invasive Phenotype in Liver Cancer.","authors":"Xiangyu Gong,Noriyoshi Ogino,M Fátima Leite,Dingyao Zhang,Zehua Chen,Ryan Y Nguyen,Raymond Liu,Emma Kruglov,Kaitlin Flores,Aidan T Cabral,Gabriel Moreira de M Mendes,Barbara E Ehrlich,Michael Mak","doi":"10.1158/0008-5472.can-24-0859","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0859","url":null,"abstract":"Physical constraints like compression influence cancer cell invasion and transcriptional dynamics in various tumors. Liver cancer is characterized by the rapid proliferation of tumor cells within a densely packed tissue matrix, subjecting the cancer cells to crowding and compression. The highly dysregulated mechanical environment highlights the need to elucidate the broader impact of compression on liver cancer development and evolution. In this study, we investigated and described a unique adaptive response of liver cells to prolonged compression. Liver cells presented significant transcriptional changes due to compression, including the loss of liver-specific markers and enrichment of epithelial-to-mesenchymal transition genes. Compression elevated Rac1 activity, which promoted cellular protrusions and YAP nuclear translocation and maintained cell viability under mechanical stress. Furthermore, compression disrupted intracellular calcium signaling, leading to resistance to apoptosis. Counteracting the effects of compression by inhibiting Rac1 or manipulating intracellular calcium facilitated death of compression-adapted cells. This study highlights compression as a critical biophysical signal in the tissue microenvironment that can induce cell state transitions and disease-driving phenotypes in the liver.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"41 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087749","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":"Genomic Analyses Reveal the Evolving Characteristics of Intestinal Metaplasia and Gastric Cancer","authors":"Xianfeng Xu, Caiwang Yan, Lijun Bian, Zhe Li, Yuhui Yu, Xia Zhu, Yun Gao, Hao Xu, Fengyuan Li, Yao Liu, Ping Sun, Zheng Wang, Yao Fu, Yue Jiang, Juncheng Dai, Hongxia Ma, Zhibin Hu, Hongbing Shen, Gang Li, Cheng Wang, Guangfu Jin","doi":"10.1158/0008-5472.can-24-4065","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4065","url":null,"abstract":"Intestinal metaplasia (IM) represents a precancerous condition associated with an increased gastric cancer (GC) risk. A better understanding of whether and how precancerous lesions progress to GC is crucial for patient stratification and personalized prevention. Here, we reconstruct evolutionary trajectories of genomic alterations in 330 multi-region matched samples of IM and tumors from 93 GC patients. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable (GS) patients. IM from GS patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. \"Maintained\" genes (TP53, APC, and PIK3CA) were commonly altered in IM and matched GC samples in both IGC and DGC, while CDH1 mutations were specific to DGC. \"Maintained\" mutations in IM accelerated GC progression. Alterations in \"IM favored\" genes (MUC6, CFTR, BMP6, and MTRR) were associated with IM development but were negatively selected in GC. Interestingly, MUC6 mutations were enriched in specific pit cells with upregulation of GKN1 and GKN2. The remaining genes were \"GC favored\" and showed high heterogeneity in GC. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"64 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067152","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":"Cells keep diverse company in diseased tissues","authors":"Kieran R. Campbell, Aleksandrina Goeva","doi":"10.1158/0008-5472.can-25-2070","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2070","url":null,"abstract":"Emerging spatial profiling technologies have revolutionized our understanding of how tissue architecture shapes disease progression, yet the contribution of cellular diversity remains underexplored. Here, Ding and colleagues introduce multiomics and ecological spatial analysis (MESA), an ecology-inspired framework that integrates spatial and single-cell expression data to quantify tissue diversity across multiple scales. MESA both identifies distinct cellular neighborhoods and computes a variety of diversity metrics alongside the identification of diversity “hotspots”. Applied to human tonsil tissue, MESA revealed previously undetected germinal center organization, while in spleen tissue of a murine lupus model, MESA highlights increasing cellular diversity with disease progression. Importantly, diversity hotspots do not correspond to conventional compartments identified by existing methods, presenting an orthogonal metric of spatial organization. In colorectal cancer, MESA’s diversity metrics outperformed established subtypes at predicting patient survival, while in hepatocellular carcinoma, multi-omic integration identified significantly more ligand-receptor interactions between immune cells compared to single-modality analysis. This work establishes cellular diversity within tissues as a critical correlate of disease progression and underscores the value of multi-omic integration in spatial biology.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067154","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":"Retraction: HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma.","authors":"Siong-Seng Liau, Amarsanaa Jazag, Edward E Whang","doi":"10.1158/0008-5472.CAN-25-0888","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0888","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 10","pages":"1946"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076189","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":"Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation","authors":"Islam E. Elkholi, Amélie Robert, Camille Malouf, Joshua L. Wu, Hellen Kuasne, Stanislav Drapela, Graham Macleod, Steven Hébert, Alain Pacis, Virginie Calderon, Claudia L. Kleinman, Ana P. Gomes, James V. Alvarez, Julio A. Aguirre-Ghiso, Morag Park, Stéphane Angers, Jean-François Côté","doi":"10.1158/0008-5472.can-23-2654","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2654","url":null,"abstract":"Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07 cells displayed a unique dependency on class III PI3K (PIK3C3). Unexpectedly, 4T07 cells exhibited higher mechanistic target of rapamycin complex 1 (mTORC1) activity than 4T1 cells due to lysosome-dependent signaling occurring at the cell periphery. Pharmacologic inhibition of PIK3C3 suppressed this phenotype in the 4T1-4T07 models as well as in human breast cancer cell lines and a breast cancer patient-derived xenograft. Furthermore, inhibiting PIK3C3 selectively reduced metastasis burden in the 4T07 model and eliminated dormant cells in a HER2-dependent murine breast cancer dormancy model. These findings suggest that PIK3C3-peripheral lysosomal signaling to mTORC1 may represent a targetable axis for preventing dormant cancer cell–initiated metastasis in patients with breast cancer. Significance: Dormancy-prone breast cancer cells depend on the class III PI3K to mediate peripheral lysosomal positioning and mTORC1 hyperactivity, which can be targeted to blunt breast cancer metastasis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066509","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":"FADD Functions as an Oncogene in Chr11q13.3-Amplified Head and Neck Squamous Cell Carcinoma.","authors":"Yang Zheng,Yinan Chen,Xiaoyan Meng,Li Zhang,Yanni Ma,Rong Zhou,Shuiting Fu,Heng Chen,Xinyang Xuanyuan,Ruixin Jiang,Pengcong Hou,Xiaomeng Song,Yanqiu Wang,Jingjing Sun,Wuchang Zhang,Jiang Li,Zhonglong Liu,Zhiyuan Zhang,Hanlin Zeng,Yue He","doi":"10.1158/0008-5472.can-24-2562","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2562","url":null,"abstract":"Chromosomal 11q13.3 amplification is the most common gene copy-number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell-cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification. Using CRISPR-based gene knockout screening of genes located in chr11q13.3, we found that loss of the gene encoding the Fas-associated death domain (FADD) protein, a well-recognized adapter to caspase-8 that induces cell apoptosis, significantly reduced cancer cell proliferation. FADD expression was elevated in chr11q13.3-amplified tumors and correlated with poor prognosis. RNA sequencing, mass spectrometry, and proteomics analyses revealed a direct relationship between FADD and the DNA helicase MCM5 in the S phase. FADD and cyclin D1 acted at different stages of the cell cycle to synergistically induce proliferation, and caspase-8 deficiency was required for the oncogenic activity of FADD. In a patient-derived xenograft model with chr11q13.3 amplification, combined administration of the DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a nonclassic oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification. Significance: FADD promotes progression of tumors with chr11q13.3 amplification by binding to the DNA helicase complex, which can be targeted in combination with cyclin D1 as a viable therapeutic strategy for HNSCC patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"40 1","pages":"1909-1927"},"PeriodicalIF":11.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982424","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}