Cancer research最新文献

{"title":"Multiomics Dissection Reveals Natural Killer Cell-CD8+ T-cell Cooperation in Shaping an Immunostimulatory Tumor Microenvironment.","authors":"Kanako Shimizu, An Sanpei, Yan Liu, Takuya Ishibashi, Marin Yanagawa, Hiroshi Nakazato, Jun Shinga, Shogo Ueda, Satoru Yamasaki, Shin-Ichiro Fujii","doi":"10.1158/0008-5472.CAN-25-4957","DOIUrl":"10.1158/0008-5472.CAN-25-4957","url":null,"abstract":"<p><p>Immune evasion remains a major barrier to effective immunotherapy in cancer. Coordinated activation of different immune cell types shapes immune responses within the tumor microenvironment (TME). In this study, we uncovered a spatiotemporal synergy between cytotoxic T lymphocytes (CTL) and natural killer (NK) cells in tumors with low T-cell infiltration. An integrative multiomics approach combining spatial transcriptomics, single-cell RNA sequencing, and high-dimensional flow cytometry demonstrated that vaccination, capable of activating both innate and adaptive immunity, rapidly reshapes the TME. Early infiltration of IRF8+KLRG1+ NK cells established a chemokine-rich niche together with myeloid cells that promoted the recruitment of antigen-primed CXCR3+ CTLs. The accompanying inflammatory monocyte recruitment and dendritic cell activation led to the coordinated structural and chemotactic remodeling of the TME. Functionally, NK-CTL clustering at the tumor margin was associated with enhanced cytotoxic activity and sustained immune engagement. These spatially organized immune interactions involved CCR5-CCL5 and CXCR3-CXCL9 signaling pathways that coordinate communication between innate and adaptive immune compartments. Together, these findings reveal a previously unrecognized NK-CTL cooperative program that promotes the transition of poorly infiltrated tumors toward an inflamed, immune-responsive state. More broadly, this study illustrates how spatially resolved multiomics approaches can uncover immune interactions and provides a conceptual framework for designing next-generation immunotherapies that mobilize coordinated innate and adaptive immunity.</p><p><strong>Significance: </strong>Early infiltration of NK cells followed by T-cell accumulation reshapes the tumor microenvironment to promote antitumor immunity following vaccination, providing a mechanistic rationale for the development of effective vaccine-based immunotherapy strategies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4873-4890"},"PeriodicalIF":22.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663513","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":"ScanTCR Enables Early Cancer Detection by Repertoire-Scale Representation of Cancer-Associated T-Cell Receptors in Peripheral Blood","authors":"Jinwei Zhang, Yideng Cai, Jinhao Que, Zuxiang Wang, Jing Ma, Yilin Wang, Xiyun Jin, Wenyi Yang, Meng Luo, Zheng Wei, Guangfu Xue, Rongrong Yang, Fenglan Pang, Yi Hui, Wenyang Zhou, Renjie Tan, Pingping Wang, Haoxiu Sun, Zhaochun Xu, Qinghua Jiang","doi":"10.1158/0008-5472.can-26-1087","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1087","url":null,"abstract":"T cells initiate anticancer immune responses at an early stage of tumorigenesis, thus enabling dynamic monitoring of peripheral blood T-cell receptor (TCR) repertoire changes as a promising strategy for early cancer detection. However, current TCR-based cancer detection methods focus on limited high-frequency TCRs instead of repertoire-scale representation, overlooking numerous crucial cancer-associated TCRs (caTCRs). Herein, we developed ScanTCR, a computational framework for early cancer detection that introduces a reference-guided repertoire-scale encoding method capable of incorporating all TCRs. ScanTCR exhibited remarkable precision in distinguishing cancer patients from non-cancer individuals using peripheral blood TCR. In a pan-cancer analysis encompassing seven cancer types, ScanTCR demonstrated robust performance in detecting both cancer types included in the training data and unseen cancer types, surpassing state-of-the-art TCR-based methods. Furthermore, ScanTCR identified caTCRs whose corresponding T cells exhibit enhanced cellular immune capacity. Collectively, this work proposes a TCR-based approach enabling repertoire-scale representation of immune receptors for noninvasive early cancer detection.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086341","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":"Exercise Modulates Microbial Metabolites and Induces Stromal Remodeling in Pancreatic Cancer.","authors":"Sumedha Pareek, Robin D Wright, Riccardo Ballarò, Cayla Xue, Thais F Bartelli, Vidhi Chandra, Le Li, Justina Ortiz, Truong Lam, Hetal Patel, Jonghae Lee, Pradeep Shrestha, Hannah Savage, Olivereen Le Roux, Haoyue Liu, Tamara Vallejo-Schmidt, Ryan De Maleki, Vasanta Putluri, Nagireddy Putluri, Joseph F Petrosino, Jared K Burks, Javier A Gomez, Jlenia Guarnerio, Matthew H G Katz, An Ngo-Huang, Laura R Prakash, Nathan H Parker, Maria Q B Petzel, Lin Tan, Seyda Baydogan, Florencia McAllister, Keri L Schadler","doi":"10.1158/0008-5472.CAN-25-5143","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-5143","url":null,"abstract":"<p><p>Exercise induces a variety of changes in the tumor microenvironment, with beneficial effects in several tumor types. However, a better understanding of the clinical effects of exercise and mediating mechanisms is needed to maximize the utility of exercise for patients. In this study, we analyzed tumors from patients with pancreatic ductal adenocarcinoma (PDAC) in the PancFit trial and identified an exercise-induced reduction in cells expressing α-smooth muscle actin (αSMA). Interrogation of changes in tumor stromal composition with exercise in a murine PDAC model revealed a microbially influenced reduction in αSMA+ cells and Il6-expressing inflammatory cancer-associated fibroblasts (iCAF). Cholic acid, a microbial bile acid, was increased in both patients and murine models with exercise, as a potential mediator of exercise-induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 expression, supporting a stromal remodeling effect of physical activity. In summary, this study demonstrates that the antitumor effect of exercise includes stromal remodeling, which is affected by microbial metabolites.</p><p><strong>Significance: </strong>Exercise-induced changes in cancer associated fibroblasts vary with microbiome composition, which may explain the heterogeneity in tumor responses to exercise and could guide future exercise trials in cancer patients.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"OF1-OF17"},"PeriodicalIF":22.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103598","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":"MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation.","authors":"Zeyu Yan, Dan Wu, Jingyun Wu, Caiyu Shi, Mengmeng Feng, Yu Li, Gang Wang, Xinwei Liu, Jibin Li, Guoqing Qi, Xianli He, Tingting Ren, Jinliang Xing","doi":"10.1158/0008-5472.CAN-26-0575","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-26-0575","url":null,"abstract":"<p><p>Tumor cells commonly exhibit a preferential uptake of glutamine to support the heightened metabolic demands. However, the therapeutic potential of targeting glutamine metabolism is severely limited by the heterogeneous responses of cancer cells to glutamine deprivation. In this study, we identified a ribophagy-adenosine-MYC positive feedback loop that was activated and determined cell fate under glutamine deprivation. In sensitive cells, highly expressed MYC acted as a scaffold to recruit Unc-51 like autophagy activating kinase 1, which phosphorylated ribosomal protein L12 to initiate ribophagy. This process drove extensive rRNA catabolism and a burst of reactive oxygen species, ultimately leading to cell death. Moreover, adenosine generated during this cascade enhanced MYC expression via its 3'-UTR region, locking the loop into a self-reinforcing hyperactivated state. In contrast, tolerant cells exhibited lower MYC expression, which constrained the loop to a low-activity and subcritical steady state, thereby enabling survival under glutamine deprivation. Consequently, MYC-high tumors were vulnerable to glutaminase inhibition alone (CB-839), while MYC-low tumors required combination therapy with CB-839 and a pro-oxidant (elesclomol) to achieve tumor eradication. This study establishes MYC expression as a key determinant of sensitivity to glutamine deprivation, reveals the central role of ribophagy within the glutamine deprivation-triggered positive feedback loop, and uncovers a non-canonical, scaffold-like function of MYC in rRNA catabolism. These findings highlight a potential combination strategy to overcome a major bottleneck in targeting glutamine metabolism.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":22.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079670","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":"Inhibition of Translesion DNA Synthesis Sensitizes BRCA-Deficient Ovarian Cancer to PARP Inhibitors","authors":"Na Li, Kousalya Lavudi, Qianyun Ge, Yajing Yang, Linzhou Wang, Aidan Li, Ananya Banerjee, Yue Xu, Brandon Steiger, Eman A. Ahmed, Dayong Wu, Xuetao Bai, Jessica Miao, Xiaoli Zhang, Zaibo Li, Karuppaiyah Selvendiran, Junran Zhang, Floor J. Backes, Shuiying Hu, Qi-En Wang","doi":"10.1158/0008-5472.can-26-1379","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1379","url":null,"abstract":"Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality to treat BRCA1/2-mutated ovarian cancer, yet clinical responses are often incomplete and resistance frequently emerges. PARPi exert cytotoxic effects by inhibiting single-strand break repair and trapping PARP on DNA, which impedes replication fork progression and generates lethal double-strand breaks. However, tumor cells can mitigate these effects through activation of alternative DNA repair mechanisms. Here, we investigated the role of translesion synthesis (TLS), a DNA damage tolerance pathway in which specialized polymerases bypass DNA lesions to sustain replication, in mediating PARPi resistance using homologous recombination (HR)-deficient epithelial ovarian cancer cell lines, patient-derived organoids (PDOs), and orthotopic xenograft models. PARPi treatment markedly slowed replication fork progression and activated TLS. Genetic depletion of the TLS scaffold protein REV1 and TLS polymerase η (Polη, encoded by POLH) exacerbated olaparib-induced replication stress, impaired fork restart, and sensitized BRCA1/2-deficient cells to PARPi. Importantly, pharmacological TLS inhibition with JH-RE-06 synergized with olaparib to enhance cytotoxicity in HR-deficient cells and PDOs, while in vivo combination therapy delayed or prevented resistance and achieved sustained tumor regression. Notably, TLS blockade also suppressed the emergence of BRCA2 reversion mutations in BRCA2-mutated ovarian cancer cells and prevented the development of olaparib resistance during chronic olaparib exposure. Collectively, these findings demonstrate that TLS, particularly Polη-dependent bypass, is a critical mechanism enabling replication fork rescue and survival under PARPi therapy. Targeting TLS provides a promising therapeutic strategy to augment PARPi efficacy and prevent resistance in BRCA-deficient ovarian cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"23 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070939","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 ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia","authors":"Xinrong Xiang, Baozhu Luo, Lei Zhao, Jing Sui, Yi Wu, Jiasheng Huang, Song Liu, Hexian Li, Fangfang Wang, Mengran Chen, Ying Qu, Aiping Tong, Chong Chen, Yu Wu, Youfu Luo","doi":"10.1158/0008-5472.can-26-0477","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0477","url":null,"abstract":"Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic–immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070937","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":"Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition","authors":"Thi Thinh Nguyen, Jane Ding, Mohit Bansal, Sunil Sudarshan, Han-Fei Ding","doi":"10.1158/0008-5472.can-26-1063","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1063","url":null,"abstract":"The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD⁺/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2–eIF2α–ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD⁺/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD⁺ regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD⁺ regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"476 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070938","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 Paired Tumor Organoid-Stroma Biobank Reveals PLAU⁺ Fibroblasts as Drivers of Chemoresistance in Lung Adenocarcinoma","authors":"Siqi Li, Ze Zhang, Quankun Lv, Yunfeng Cao, Chunhui Song, Jinghao Liang, Yi-Fan Qi, Ziyuan Duan, Yalong Wang, Ye-Guang Chen","doi":"10.1158/0008-5472.can-26-1323","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1323","url":null,"abstract":"Chemotherapy is a standard treatment for lung adenocarcinoma (LUAD), yet the efficacy is often limited, highlighting the need to elucidate and the underlying mechanisms of chemoresistance. Given the important role of the tumor microenvironment in LUAD progression, we established a biobank of patient-derived LUAD organoids (LCOs) paired with cancer-associated fibroblasts (CAFs) from treatment naïve tumors and found that co-culture with CAFs reduced drug sensitivity of LCOs. Plasminogen activator urokinase (PLAU) was identified as a specific marker of chemoresistance-associated CAFs linked with poor survival in LUAD patients. Tumor cells induced polarization of fibroblasts toward a PLAU+ chemoresistant state that secreted CXCL5 to upregulate the ER chaperone calmegin (CLGN) in tumor cells. CLGN ablation restored drug sensitivity, whereas CLGN expression was elevated in chemotherapy-resistant LUAD and correlated with pathological progression. Together, these findings identify the PLAU⁺ CAF-CXCL5-CLGN axis that drives LUAD chemoresistance and suggest that CLGN inhibition could be a promising therapeutic strategy to overcome chemoresistance in advanced LUAD.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"25 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070934","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 A108: Circulating GDF-15 reflects KRAS variant and co-mutation biology in advanced pancreatic ductal adenocarcinoma","authors":"Abrahm Levi, Sargis Hovhannisyan, Maria Cechini, Jun Gong, Andrew E. Hendifar, Arsen Osipov","doi":"10.1158/1538-7445.pancreatic26-a108","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a108","url":null,"abstract":"Background: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that is frequently elevated in pancreatic ductal adenocarcinoma (PDAC) and has been implicated in cancer cachexia, systemic inflammation, and poor clinical outcomes. Preclinical studies suggest that oncogenic KRAS signaling can regulate GDF-15 expression through downstream MAPK and stress-response pathways, raising the possibility that distinct KRAS alleles may influence circulating GDF-15 levels. Given the high prevalence of cancer cachexia in PDAC, we evaluated associations between serum GDF-15 levels, and KRAS variants and TP53 gene mutations in patients with PDAC. Methods: Tumor mutation status and GDF-15 concentrations were retrospectively analyzed across 48 PDAC patients enrolled on an institutional biobank (Pro00054363). GDF-15 levels were measured using an MSD R-Plex Human GDF-15 assay. Welch’s t-tests were used to assess differences in GDF-15 levels between mutation groups. Results: In the advanced PDAC cohort, mean GDF-15 concentrations were 1,940 pg/mL for KRAS G12R (n=6), 3,414 pg/mL for KRAS G12D (n=26), and 3,506 pg/mL for KRAS G12V (n=13). Low GDF-15 concentrations (&amp;lt;800 pg/mL), defined in a previous analysis done by our group using a mean of 598 +/- 304 pg/mL for non-cancer patients, was observed in 2 of 6 patients (33.3%) with KRAS G12R tumors compared with 2 of 42 patients (4.8%) in the All-other KRAS comparator cohort. Low GDF-15 was associated with significant increased odds of KRAS G12R status (OR 21.0, 95% CI 1.54-285.70; logistic-regression p=0.022; Fisher’s exact p=0.036). TP53 co-mutation (n=33) was associated with significantly higher mean GDF-15 concentrations compared with TP53 wild-type tumors (n=15) (3,709 pg/mL vs. 1,956 pg/mL, p&amp;lt;0.05). Conclusion: Patients with advanced PDAC harboring KRAS G12R mutations demonstrated lower circulating GDF-15 concentrations than those with KRAS G12D or G12V mutations. A subset of KRAS G12R tumors exhibited GDF-15 levels within the range observed in non-cancer patients, suggesting a distinct systemic biologic phenotype. These findings support further investigations of circulating GDF-15 as a noninvasive biomarker of PDAC biology. These findings suggest G12R tumors may induce less systemic stress/cachexia; however, this needs to be evaluated in a larger cohort. Citation Format: Abrahm Levi, Sargis Hovhannisyan, Maria Cechini, Jun Gong, Andrew E. Hendifar, Arsen Osipov. Circulating GDF-15 reflects KRAS variant and co-mutation biology in advanced pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr A108.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048674","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 B010: RUNX1/2-mediated chromatin accessibility governs the activation of cancer associated fibroblasts in pancreatic cancer","authors":"Chang-il Hwang","doi":"10.1158/1538-7445.pancreatic26-b010","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b010","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains the deadliest cancer with only 13% of five-year survival rate in patients. However, effective drug delivery and administration of immunotherapy have been limited due to the dense fibrotic stroma in PDAC tumor microenvironment, majorly contributed by cancer-associated fibroblasts (CAFs). Unfortunately, targeting CAFs has not yet been successful due to the lack of understanding in CAF activation, heterogeneity, and plasticity. Of note, CAFs do not genetically differ from their origins, and they are interconvertible depending on external factors and signaling cues. This plasticity feature suggests that CAFs activation is regulated by epigenetic reprogramming. Using ATAC-seq and innovative PDAC organoid-CAF co-culture models, we revealed distinct chromatin accessibility profiles of two major CAF subtypes, myofibroblasts (myCAF) and inflammatory fibroblasts (iCAFs) in vitro. In parallel, snATAC-seq analysis on both patient samples and mouse models also indicated the role of chromatin accessibility in differentiating CAF subtypes. Interestingly, we discovered a universal inflammatory-to-fibroblastic process, in which fibroblasts were initially activated into iCAFs and gradually transitioned into late-stage LRRC15+ myCAFs. Notably, this activation towards myofibroblast is tightly regulated by RUNX1/2 transcription factors. Both pharmacological inhibition and genetic perturbation targeting RUNX1/2 significantly repressed CAF activation into either myCAFs or iCAFs and suppressed tumor organoid-fibroblast crosstalk in co-culture settings. Additionally, knocking out of Runx1/2 in fibroblasts markedly reduced collagen deposition and tumor growth in mice co-transplanted orthotopically with tumor organoids and fibroblasts. Overall, our study demonstrates the epigenetic basis of CAF plasticity and suggests a therapeutic strategy targeting the RUNX1/2 family to remodel the stroma and improve treatment outcomes. Citation Format: Chang-il Hwang. RUNX1/2-mediated chromatin accessibility governs the activation of cancer associated fibroblasts in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B010.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"59 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048601","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}