Cancer research最新文献

{"title":"Bacterial Therapeutics: Addressing the Affordability Gap in Cancer Therapy","authors":"Kejsi Prifti, Chiswili Yves Chabu, Koichi S. Kobayashi, Jianxun Song, Arum Han, Paul de Figueiredo","doi":"10.1158/0008-5472.can-25-0870","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0870","url":null,"abstract":"The global cancer care burden is projected to reach $25 trillion by 2050, with the United States experiencing increasing costs from $57 billion to $209 billion. The application of expensive cellular immunotherapies (exceeding $300,000 per treatment) will exacerbate escalating cancer care costs. Bacteria-based immunotherapies are emerging as safe, lower-cost alternatives. Recent synthetic biology and artificial intelligence advances may enable the development of next-generation bacterial therapies with reduced toxicity. These systems can bypass cold chain constraints and be manufactured at <$10/dose, offering more than 30,000-fold cost savings compared to cell therapies. Therefore, as they evolve, bacterial therapies could transform cancer care by improving outcomes and alleviating global healthcare economic pressures.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629826","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 and Single-Cell Analyses Characterize Patient-Derived Tumor Organoids to Enable Personalized Therapy for Head and Neck Squamous Cell Carcinoma.","authors":"Jung Hyun Um, Yueyuan Zheng, Qiong Mao, Chehyun Nam, Hua Zhao, Yoon Woo Koh, Su-Jin Shin, Young Min Park, De-Chen Lin","doi":"10.1158/0008-5472.CAN-24-2850","DOIUrl":"10.1158/0008-5472.CAN-24-2850","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) remains a significant health burden because of tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. In this study, we enrolled 31 patients with HNSCC for the establishment of patient-derived tumor organoids (PDO), which faithfully maintained the genomic features and histopathologic traits of the primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, with ex vivo drug sensitivity correlating with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor transcriptional heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition-like ITH program was associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin as a potential regulator of the hybrid epithelial-mesenchymal state. Moreover, amphiregulin contributed to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine.</p><p><strong>Significance: </strong>Profiling of patient-derived organoids uncovers intertumoral heterogeneity and a hybrid epithelial-mesenchymal transition program conferring cisplatin resistance and highlights amphiregulin as a regulator of cellular plasticity and potential therapeutic target for HNSCC treatment.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2726-2742"},"PeriodicalIF":12.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966134","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":"FADD Activation in Hepatocellular Carcinoma Potentiates CD8+T Cell Responses and Sensitizes to Immune Checkpoint Inhibitors","authors":"Jiahuan Lu, Thomas Ting-Hei. Chan, Yun Wang, Jingya Wang, Zhewen Xiong, Jingqing Li, Yixuan Zhang, Huanyu Wang, Jintian Chen, Weiqin Yang, Jing Wang, Yalin Tu, Howard H.W. Leung, Raymond Wai Ming. Lung, Wei Kang, Man Tong, Dan Michelle. Wang, Qi-Nian Wu, Zhao-Lei Zeng, Alfred Sze Lok. Cheng, Ka-Fai To, Anthony W.H. Chan, Jingying Zhou","doi":"10.1158/0008-5472.can-24-3854","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3854","url":null,"abstract":"Turning immunologically “cold” tumors “hot” is required for effective immune checkpoint inhibitor (ICI) treatment in hepatocellular carcinoma (HCC). Here, we identified Fas-associated death domain (FADD) as a key molecule upregulated in HCC with dense tumor-infiltrating CD8+ T cells and better response to ICIs. CRISPR-mediated knockout of Fadd in murine HCC cells led to increased tumor weights in immunocompetent, but not immunodeficient, mice. FADD deficiency also led to decreased intratumoral infiltration of CD8+ T cells and lower production of IFN-γ and TNF-ɑ. Mechanistically, phosphorylated FADD translocated into the nucleus where it interacted with Sam68 to upregulate NF-κB-induced transcription of CCL5, thereby promoting CD8+ T cell recruitment. Treatment with anti-PD-1 triggered FADD phosphorylation in ICI-sensitive tumors, which was not observed in ICI-resistant tumors. FADD activation through genetic or pharmacologic approaches overcame ICI resistance in orthotopic and spontaneous HCC mouse models in vivo. Together, these findings provide insights into combinatory immunotherapy approaches for HCC patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"23 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629832","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":"A Four Amino Acid Intracellular Motif of VISTA Blocks Growth Receptor Signaling in Cancer Cells to Induce Tumor Suppression","authors":"Yan Zhao, Tina Andoh, Fatima Charles, Priyanka Reddy, Kristina Paul, Harsh Goar, Ishrat Durdana, Caiden J. Golder, Ashley N. Hardy, Marisa M. Juntilla, Soo-Ryum Yang, Chieh-Yu Lin, Idit Sagiv-Barfi, Benjamin S. Geller, Stephen Moore, Dipti Thakkar, Jerome D. Boyd-Kirkup, Yan Peng, James M. Ford, Melinda L. Telli, Song Zhang, Allison W. Kurian, Robert B. West, Tao Yue, Andrew M. Lipchik, Michael P. Snyder, Joshua J. Gruber","doi":"10.1158/0008-5472.can-24-4774","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4774","url":null,"abstract":"VISTA is a key immune checkpoint receptor under investigation as a target for cancer immunotherapy. However, a better understanding of the signaling mechanisms of VISTA is needed to optimize the therapeutic potential. Here, we identified a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. A class of triple-negative breast cancers (TNBC) with high VISTA expression and low proliferative index was identified and characterized. The NPGF motif bound to the adapter protein NUMB and recruited Rab11 endosomal recycling machinery. The NPGF motif sequestered NUMB at endosomes, which interfered with EGFR trafficking and signaling to suppress tumor growth. These tumor suppressive effects did not require canonical VISTA ligands or a functioning immune system. Mutation of the VISTA NPGF domain reverted VISTA-induced growth suppression in multiple breast cancer mouse models. The NPGF motif was also required for response of VISTA+ TNBCs to VISTA-blocking antibodies. These results define a mechanism by which VISTA recruits adapter proteins to control malignant epithelial cell growth and signaling. They also define distinct intracellular residues that are critical for response to therapeutic antibodies that could be exploited to improve immunotherapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629827","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":"Selective Alanine Transporter Utilization is a Therapeutic Vulnerability in ARID1A-Mutant Ovarian Cancer","authors":"Hao Nie, Liping Liao, Rafal J. Zielinski, Javier A. Gomez, Akshay V. Basi, Erin H. Seeley, Lin Tan, Agnes Julia. Bilecz, Wei Zhou, Heng Liu, Chen Wang, Shuai Wu, Yuan Qi, Taito Miyamoto, Federica Severi, Aaron R. Goldman, Shengqing Gu, Anil K. Sood, Amir A. Jazaeri, Ronny Drapkin, Daniel T. Claiborne, Nan Zhang, Philip L. Lorenzi, Jared K. Burks, Ernst Lengyel, Eyal Gottlieb, Rugang Zhang","doi":"10.1158/0008-5472.can-25-0654","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0654","url":null,"abstract":"Subunits of the SWI/SNF chromatin remodeling complex are altered in ~20% of human cancers. Exemplifying the alterations is the ARID1A mutation that occurs in ~50% ovarian clear cell carcinoma (OCCC), a disease with limited therapeutic options. Here, we showed that ARID1A mutations create a dependence on alanine by regulating alanine transporters to increase intracellular alanine levels. ARID1A directly repressed alanine importer SLC38A2 and simultaneously promoted alanine exporter SLC7A8. ARID1A inactivation increased alanine utilization predominantly in protein synthesis and passively through the tricarboxylic acid cycle. Indeed, ARID1A-mutant OCCCs were hyper-sensitive to inhibition of SLC38A2. In addition, SLC38A2 inhibition enhanced chimeric antigen receptor-T cell assault in vitro and synergized with immune checkpoint blockade using an anti-PD-L1 antibody in a genetically engineered mouse model of OCCC driven by conditional Arid1a inactivation in a CD8+ T-cell dependent manner. These findings suggest that targeting alanine transport alone or in combination with immunotherapy may represent an effective therapeutic strategy for ARID1A-mutant cancers.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"39 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629828","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":"RIT1 Drives Oncogenic Transformation and is an Actionable Target in Lung Adenocarcinoma","authors":"Alessandro M. Mozzarelli, Antonio Cuevas-Navarro, Emily G. Shuldiner, Martha Vega, Walid K. Chatila, Jierui Xu, Henry S. Walch, Yuzhe Niu, Dmitri A. Petrov, Nikolaus Schultz, Anatoly Urisman, Charles M. Rudin, Monte M. Winslow, Pau Castel","doi":"10.1158/0008-5472.can-24-3819","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3819","url":null,"abstract":"RIT1 is a small GTPase of the RAS family, and RIT1 mutations have been identified in lung cancer, leukemias, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased protein levels due to impaired proteolysis, resulting in dysregulation of RAS/MAPK signaling and other pathways. Here, we documented the diversity of RIT1 mutations in human lung cancer and showed that physiological expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Evaluation of complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway revealed that RIT1 M90I tumors are sensitive to SHP2 inhibitors and RAS nucleotide exchange inhibition. Additionally, a proof-of-concept chemical biology approach identified that RAS tri-complex inhibitors bind directly to GTP-bound RIT1, resulting in tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611220","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":"AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.","authors":"Daniela Conticelli,Marco Volante,Filippo Pietrantonio,Claudia Orrù,Martina Olivero,Alessia Nottegar,Felice Borghi,Gian L Baiocchi,Giovanni Crotti,Uberto Fumagalli Romario,Giovanni De Manzoni,Rossella Reddavid,Roberta Porporato,Dinçer Kılıç,Rebecca Ghione,Erika Calabrò,Russell Petty,Simona Corso,Silvia Giordano,Cristina Migliore","doi":"10.1158/0008-5472.can-25-0073","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0073","url":null,"abstract":"EGFR is a potential therapeutic target in gastroesophageal cancer. However, negative results from several phase II/III clinical trials have hindered the approval of EGFR inhibitors for treating gastroesophageal adenocarcinoma. Preclinical and clinical results have shown that EGFR targeting is effective in patients with gastroesophageal adenocarcinoma harboring EGFR amplification. Retrospective analyses also suggest that a subset of patients with gastroesophageal adenocarcinoma lacking EGFR amplification may benefit from the treatment, thus underscoring the need to identify reliable predictive biomarkers of response. Through the screening of 27 gastroesophageal adenocarcinoma primary cancer cell lines and 10 patient-derived xenograft models, we identified a subset of gastroesophageal adenocarcinoma lacking EGFR quantitative alterations but sensitive to EGFR targeting. Molecular characterization of the sensitive models revealed overexpression of the EGFR ligand amphiregulin (AREG) or epiregulin (EREG). Post hoc analysis of patients on the Cancer Esophagus Gefitinib trial treated with the EGFR inhibitor gefitinib demonstrated a significant correlation between overall survival and AREG/EREG expression level. No predictive power of EGFR ligand expression was observed in the presence of KRAS mutations. In conclusion, this study proposes the existence of a subgroup of patients with gastroesophageal adenocarcinoma with susceptibility to EGFR inhibition driven by overexpression of the EGFR ligands AREG and EREG.SIGNIFICANCEElevated levels of AREG or EREG in gastroesophageal cancer confers sensitivity to EGFR inhibition, providing a low-toxicity treatment option for the subpopulation of patients overexpressing the EGFR ligands.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"109 1","pages":"OF1-OF12"},"PeriodicalIF":11.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593979","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":"Pancreatic Neuroendocrine Tumors Secrete Apolipoprotein E to Induce Tip Endothelial Cells That Remodel the Tumor–Stroma Ratio and Promote Cancer Progression","authors":"Xin Lou, Yihua Shi, Faming Zhao, Xiaowu Xu, Yan Wang, Yi Qin, Wuhu Zhang, Zeng Ye, Fei Wang, Tian Ding, Desheng Jing, Guixiong Fan, Yue Zhang, Xuemin Chen, Jie Chen, Xianjun Yu, Junfeng Xu, Shunrong Ji","doi":"10.1158/0008-5472.can-24-2528","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2528","url":null,"abstract":"A low tumor–stroma ratio (TSR) in pancreatic neuroendocrine tumors (pNET) is associated with a significantly poorer patient prognosis. Although the tumor stroma represents an attractive therapeutic target, recent clinical trials have not been successful. In this study, we aimed to dissect the mechanisms regulating the tumor microenvironment in low TSR pNETs to identify potential therapeutic targets. Laser capture microdissection analysis revealed that stroma-rich tumors excessively secrete apolipoprotein E (ApoE) relative to stroma-poor tumors, with the specific receptor SCARB1 predominantly located on endothelial cells (EC). Single-cell analysis revealed a greater proportion of endothelial tip cells (TipEC) in stroma-rich tumors due to transformation of other types of ECs into TipECs induced by cancer cell–derived ApoE. The TipECs played crucial roles in driving pNET progression by facilitating cancer-associated fibroblast recruitment and remodeling the TSR. Mechanistically, ApoE promoted the uptake of palmitic acid by ECs and subsequently activated the transcription factor ATF6 to upregulate the PDGF pathway. Screening of six commonly used drugs for pNETs in vivo revealed that treatment with mTOR inhibitors suppressed the secretion of ApoE by cancer cells, blocking the subsequent effects of ApoE on the stromal microenvironment. Importantly, mTOR inhibitors synergistically enhanced the antitumor effects of stroma-targeting PEGPH20 in vivo in pNETs. Overall, this study revealed that cancer cell–derived ApoE could induce TipECs to remodel the TSR and that mTOR inhibitors could increase the efficacy of stroma-targeting therapies. Significance: Secretion of ApoE by pancreatic neuroendocrine tumor cells engenders a stroma-rich microenvironment, which can be reversed with mTOR inhibitors as part of combination strategies targeting the tumor stroma.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577993","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":"RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy.","authors":"Ashley V DiMarco,Mirunalini Ravichandran,Jeff Lau,Anthony Lima,Jennifer Lacap,Pablo Saenz-Lopez Larrocha,Eva Lin,Julie Weng,Luca Gerosa,Thomas Hunsaker,Yang Xiao,Monika Miś,Charles Havnar,Wennie Chen,Kai H Barck,Klara Totpal,Oded Foreman,Nicole M Sodir,Mark Merchant,Danilo Maddalo","doi":"10.1158/0008-5472.can-24-3662","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3662","url":null,"abstract":"RIT1 is a RAS-family GTPase that is mutated in 2.4% and amplified in up to 14% of lung adenocarcinoma patients. Yet, the oncogenic potential of RIT1 in the lungs has not been fully established. Consequently, patients with RIT1 alterations are considered \"oncogene-negative\" and are not eligible for any targeted therapy in the clinic. The role of RIT1 in cancer has been historically understudied due to the lack of in vitro and in vivo models harboring RIT1 alterations. In this study, we generated a murine model of RIT1M90I-mutant lung cancer. RIT1M90I expression induced tumorigenesis in the lungs, and the tumors displayed histopathological features similar to lung adenocarcinoma in humans. An unbiased chemical compound screen leveraging this model revealed a sensitivity to inhibitors of the MAPK, PI3K, and cholesterol biosynthesis pathways in RIT1 mutant cell lines. The SHP2 inhibitor, migoprotafib, in combination with other MAPK pathway targeted therapies effectively suppressed the growth of RIT1 mutant cells ex vivo and in vivo. Finally, RIT1M90I drove resistance to the KRASG12C inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, our data shows that RIT1M90I is a bona fide oncogenic driver of lung cancer and mediator of targeted therapy resistance as a co-occurring mutation and suggests that RIT1-altered cancer patients may benefit from combination treatments with a SHP2 inhibitor.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547724","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":"PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer","authors":"Beatriz Parejo-Alonso, David Barneda, Sara Maria David. Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruiz-Cañas, Quan Zheng, Jiajia Tang, Matthias M. Gaida, Ulf Schmitz, Pilar Irun, Laure Penin-Peyta, Shanthini Mary. Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng-Lay Lin, Shenghui Huang, Ming-Hsin Yang, Angel Lanas, Bruno Sainz, Christoph Thiele, Christopher Heeschen, Patricia Sancho","doi":"10.1158/0008-5472.can-24-3475","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3475","url":null,"abstract":"The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"48 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546974","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}