Cancer research最新文献

Adaptation to Volumetric Compression Drives an Apoptosis-Resistant and Invasive Phenotype in Liver Cancer. 适应体积压缩驱动肝癌细胞抗凋亡和侵袭性表型。

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-19 DOI: 10.1158/0008-5472.can-24-0859

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

{"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}

引用次数: 0

Genomic Analyses Reveal the Evolving Characteristics of Intestinal Metaplasia and Gastric Cancer 基因组分析揭示肠化生和胃癌的进化特征

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-16 DOI: 10.1158/0008-5472.can-24-4065

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

{"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}

引用次数: 0

Cells keep diverse company in diseased tissues 细胞在病变组织中有不同的同伴

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-16 DOI: 10.1158/0008-5472.can-25-2070

Kieran R. Campbell, Aleksandrina Goeva

{"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}

引用次数: 0

Retraction: HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma. 缩回：HMGA1是胰腺腺癌细胞侵袭性和体内转移潜能的决定因素。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.CAN-25-0888

Siong-Seng Liau, Amarsanaa Jazag, Edward E Whang

引用次数: 0

Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation 在易休眠的乳腺癌细胞中靶向PIK3C3-mTORC1信号抑制转移起始

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.can-23-2654

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

{"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}

引用次数: 0

FADD Functions as an Oncogene in Chr11q13.3-Amplified Head and Neck Squamous Cell Carcinoma. FADD在chr11q13 .3扩增头颈部鳞状细胞癌中作为癌基因发挥作用

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.can-24-2562

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

{"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}

引用次数: 0

Editor's Note: A Novel Role for Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 as a Determinant of Gemcitabine Chemoresistance in Pancreatic Adenocarcinoma Cells. 编者注：癌胚抗原相关细胞粘附分子6作为胰腺腺癌细胞吉西他滨化疗耐药的决定因素的新作用。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.CAN-25-0886

Mark S Duxbury, Hiromichi Ito, Eric Benoit, Talat Waseem, Stanley W Ashley, Edward E Whang

引用次数: 0

Combining STING Agonists with PARP Inhibitors Mounts an NK-Dependent Defense against Therapy-Resistant Breast Cancer. 联合STING激动剂与PARP抑制剂对治疗抵抗性乳腺癌的nk依赖性防御

IF 11.2 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.can-25-0831

Zahra Gohari,Lora Stojanovic,Feyruz V Rassool

{"title":"Combining STING Agonists with PARP Inhibitors Mounts an NK-Dependent Defense against Therapy-Resistant Breast Cancer.","authors":"Zahra Gohari,Lora Stojanovic,Feyruz V Rassool","doi":"10.1158/0008-5472.can-25-0831","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0831","url":null,"abstract":"Breast cancers with BRCA1 or BRCA2 mutations are defective in repair of DNA double-strand breaks by homologous recombination, resulting in compensatory error-prone repair that causes genomic instability. Poly(ADP-ribose) polymerase inhibitors (PARPi) are FDA-approved to treat homologous recombination-defective cancers, inducing therapy responses by synthetic lethality. PARPis increase micronuclei formation and cytosolic double-stranded DNA accumulation, activating stimulator of interferon genes (STING). Activation of STING can mediate anticancer innate immune responses by increasing T-cell infiltration into the tumor microenvironment. However, PARPi responses are not durable, and therapy resistance ensues with limited therapeutic options available for these patients. Using PARPi-sensitive and -resistant patient-derived xenografts and mouse-derived allografts, Pedretti and colleagues show in this issue of Cancer Research that the PARPi olaparib in combination with the next-generation STING agonist diABZI can overcome PARPi resistance in a manner dependent on NK cell function in the tumor microenvironment. Their study highlights a novel component of the STING-dependent innate immune response repertoire required for fighting PARPi-resistant cancer. Potent and specific next-generation STING agonists are being tested in the clinic in solid and liquid tumors, indicating a resurgence of these drugs after a long period of modest clinical activity, with a special focus on combination therapy strategies to fight therapy-resistant cancer. See related article by Pedretti et al., p. 1888.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":"1747-1749"},"PeriodicalIF":11.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982532","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}

引用次数: 0

SMARCA4 Inhibits Breast Cancer Progression and Metastasis through RHOA Suppression. SMARCA4通过抑制RHOA抑制乳腺癌进展和转移。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.CAN-24-2801

Zheng Sun, Zhuo Li, Yong Wei, Lillian Xu, Xiang Hang, Yibin Kang

{"title":"SMARCA4 Inhibits Breast Cancer Progression and Metastasis through RHOA Suppression.","authors":"Zheng Sun, Zhuo Li, Yong Wei, Lillian Xu, Xiang Hang, Yibin Kang","doi":"10.1158/0008-5472.CAN-24-2801","DOIUrl":"10.1158/0008-5472.CAN-24-2801","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is the most challenging subtype of the disease due to its aggressive nature and lack of targeted therapy options. To identify regulators of TNBC, we conducted a genome-wide CRISPR knockout screen in both three-dimensional (3D) tumor spheroid and two-dimensional cell culture models. The 3D spheroid model displayed unique potential in identifying putative tumor suppressors because of its closer mimicry of in vivo tumor growth conditions. Notably, the chromatin remodeling SWI/SNF complex emerged as a potent suppressor of tumor spheroid growth. Specifically, loss of the SWI/SNF ATPase subunit SMARCA4 promoted tumor spheroid growth with reduced compactness and enhanced primary tumor growth and metastasis across multiple TNBC models. SMARCA4 was required for the transcription of the Rho GTPase-activating factor ARHGAP29 by enhancing DNA accessibility through direct binding to its promoter. SMARCA4 loss resulted in reduced ARHGAP29 levels and hyperactive RHOA signaling, subsequently disrupting cell adhesion, facilitating the formation of a loose spheroid structure in vitro, and enhancing breast cancer growth and metastasis in vivo. These results establish SMARCA4 and SWI/SNF as tumor suppressors of TNBC through suppression of RHOA activity. Significance: CRISPR-knockout screen in 3D tumor spheroid revealed that SMARCA4, a SWI/SNF ATPase subunit, suppresses triple-negative breast cancer growth and metastasis by increasing ARHGAP29 transcription and inhibiting the RHOA signaling pathway.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1803-1818"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

"Dr. Jekyll and Mr. Hyde": AT2 Cells in Lung Regeneration and Tumor Development. “化身博士”：AT2细胞在肺再生和肿瘤发展中的作用。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-15 DOI: 10.1158/0008-5472.CAN-25-1177

Xinyuan Tong, Gen Lin, Hongbin Ji

引用次数: 0