Cancer research最新文献

{"title":"Editor's Note: A Novel Role for Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 as a Determinant of Gemcitabine Chemoresistance in Pancreatic Adenocarcinoma Cells.","authors":"Mark S Duxbury, Hiromichi Ito, Eric Benoit, Talat Waseem, Stanley W Ashley, Edward E Whang","doi":"10.1158/0008-5472.CAN-25-0886","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0886","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 10","pages":"1945"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining 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}

{"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}

{"title":"\"Dr. Jekyll and Mr. Hyde\": AT2 Cells in Lung Regeneration and Tumor Development.","authors":"Xinyuan Tong, Gen Lin, Hongbin Ji","doi":"10.1158/0008-5472.CAN-25-1177","DOIUrl":"10.1158/0008-5472.CAN-25-1177","url":null,"abstract":"<p><p>Alveolar type II cells, the primary stem cell population in the distal lung epithelium, are known to be the most common cell of origin for lung adenocarcinoma. A recent study published in Cell Stem Cell reveals that KRASG12D-mutant alveolar type II cells hijack lung regeneration programs to initiate lung adenocarcinoma, resembling \"Dr. Jekyll and Mr. Hyde\" in which their \"Jekyll\" side promotes tissue repair, whereas their \"Hyde\" side drives tumorigenesis. Sustained NF-κB activation drives lineage infidelity, enabling these mutant cells to bypass normal differentiation, remodel the surrounding microenvironment, and, ultimately, promote tumorigenesis.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1753-1754"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691283","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":"Intratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion.","authors":"Tianhao Zhang, Ying Li, Ertao Zhai, Risheng Zhao, Yan Qian, Zhixin Huang, Yinan Liu, Zeyu Zhao, Xiang Xu, Jianqiu Liu, Zikang Li, Zhi Liang, Ran Wei, Linying Ye, Jinping Ma, Qingping Wu, Jianhui Chen, Shirong Cai","doi":"10.1158/0008-5472.CAN-24-2580","DOIUrl":"10.1158/0008-5472.CAN-24-2580","url":null,"abstract":"<p><p>Intratumoral microbiota can affect the development and progression of many types of cancer, including gastric cancer. A better understanding of the precise mechanisms by which microbiota support gastric cancer could lead to improved therapeutic approaches. In this study, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment during gastric cancer malignant progression. Analysis of human gastric cancer tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum was significantly enriched in gastric cancer tissues with lymph node metastasis and correlated with a poor prognosis. F. nucleatum infection spontaneously induced chronic gastritis and promoted gastric mucosa dysplasia in mice. Furthermore, gastric cancer cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared with immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TAN) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded gastric cancer cells and activated IL17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the protumoral subtype and subsequent promotion of PD-L1 expression, further facilitating gastric cancer immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, these data uncover mechanisms by which F. nucleatum affects gastric cancer immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies. Significance: Intratumoral F. nucleatum activates NF-κB signaling to facilitate gastric cancer immune evasion by promoting tumor-associated neutrophil recruitment that sensitizes tumors to immune checkpoint blockade therapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1819-1841"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482296","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":"Retraction: Prostaglandin E2 Enhances Pancreatic Cancer Invasiveness through an Ets-1-Dependent Induction of Matrix Metalloproteinase-2.","authors":"Hiromichi Ito, Mark Duxbury, Eric Benoit, Thomas E Clancy, Michael J Zinner, Stanley W Ashley, Edward E Whang","doi":"10.1158/0008-5472.CAN-25-0887","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0887","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 10","pages":"1947"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076190","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":"Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer.","authors":"Shenghe Deng, Jun Wang, Falong Zou, Denglong Cheng, Mian Chen, Junnan Gu, Jianguo Shi, Jia Yang, Yifan Xue, Zhenxin Jiang, Le Qin, Fuwei Mao, Xiaona Chang, Xiu Nie, Li Liu, Yinghao Cao, Kailin Cai","doi":"10.1158/0008-5472.CAN-24-2892","DOIUrl":"10.1158/0008-5472.CAN-24-2892","url":null,"abstract":"<p><p>Obstructions can occur during any stage of colorectal cancer and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared with nonobstructive colorectal cancer, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. In this study, we found that colorectal cancer and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAF). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF1, TGFβ1, and CXCL8, which promoted the activation of normal fibroblasts into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating patients with colorectal cancer with risk of obstruction. Significance: Palmitic acid accumulation activates the NF-κB pathway in colorectal cancer cells to promote cytokine secretion that facilitates the generation of matrix cancer-associated fibroblasts, driving extracellular matrix remodeling and development of obstructions.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1784-1802"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482308","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":"MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.","authors":"Tianyu Qu,Lei Song,Jiali Xu,Xiyi Lu,Dandan Yin,Jiali Dai,Chen Zhang,Renhua Guo,Erbao Zhang","doi":"10.1158/0008-5472.can-23-3748","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3748","url":null,"abstract":"Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3'UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"55 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945356","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":"Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.","authors":"Kun Wang,Jingzhuo Li,Hai Zhang,Hongyan Ma,Hong-Yong Cui,Huai-Qiang Ju,Jing Zhang,Qing-Zhi Ma,Ming Zhao,Qing-Mei Zeng,Jie Zou,Xiu-Xuan Sun,Gang Nan,Meirui Qian,Lin Jing,Yiming Li,Cai-Feng Xiong,Qiu-Zi Yang,Hao Wang,Jian-Li Jiang,Zhi-Nan Chen,Liang Chen,Wan Huang","doi":"10.1158/0008-5472.can-24-3525","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3525","url":null,"abstract":"Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"57 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Suppressor Genes with Segmental Duplications are Prone to Somatic Deletions and Structural Variations.","authors":"Ziheng Huang,Lin Zhang,Huarong Chen,Xiaodong Liu,Likai Tan,Dan Huang,Yingzhi Liu,Yushan Wang,Xinyi Zhang,Alfred Sze Lok Cheng,Maggie Haitian Wang,Wei Kang,Ka-Fai To,Jun Yu,Ho Ko,Le Yu,Sunny H Wong,Tony Gin,Matthew Tak Vai Chan,Xiansong Wang,William Ka Kei Wu","doi":"10.1158/0008-5472.can-24-2225","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2225","url":null,"abstract":"Segmental duplications (SDs) are blocks of genomic DNA with high sequence homology that are hotspots for chromosomal rearrangements, coinciding with copy-number and single-nucleotide variations in the population. SDs could represent unstable genomic regions that are susceptible to somatic alterations in human cancers. Here, we aimed to elucidate the genomic locations of SDs in relation to cancer-related genes and their propensity for somatic alterations in cancer. The analysis showed that tumor suppressor genes (TSGs) were less associated with SDs compared to non-cancer genes in nearly all mammalian species. TSGs with SDs were larger in size in humans but only modestly conserved among mammals. In humans, the proportion of non-cancer genes with SDs decreased as the gene age increased. However, for TSGs, a loss of association with SDs was apparent among young genes. Pan-cancer analysis revealed that TSGs with SDs were more prone to deletions and structural variations independently of gene size. Re-analysis of publicly available experimental data further revealed that genes with SDs tended to replicate late and were more likely to undergo the error-prone mitotic DNA synthesis upon replication stress. In conclusion, the loss of SDs from TSGs during mammalian evolution protects against tumor formation by reducing somatic alterations.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"96 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945357","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}