Cancer research最新文献

{"title":"Abstract A077: Integrated biomarker analysis of circulating tumor cells, circulating tumor DNA and extracellular vesicles in a single blood draw: Longitudinal monitoring for pancreatic cancer","authors":"Yu-Shu Cheng, Yin Zou, Ashleigh Montle, Shamileh Fouladdel, Anders Bogard, Nicole Peterson, Vaibhav Sahai, Sunitha Nagrath","doi":"10.1158/1538-7445.pancreatic26-a077","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a077","url":null,"abstract":"Introduction: The high fatality of pancreatic cancer is primarily attributed to late-stage diagnosis and high recurrence rates. Among patients eligible for resection surgery, recurrence rates reach approximately 70% with a median survival of 27.9 months, highlighting the urgent need to longitudinally monitor these patients and identify those requiring more intensive intervention to prevent relapse. Liquid biopsy is a promising approach that detects blood biomarkers with high sensitivity to tumor dynamics than conventional imaging, while enabling longitudinal monitoring through minimally invasive, repetitive sampling. This study aims to develop an integrated workflow for the simultaneous analysis of blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles (tEVs). The end goal is to construct a multimodal prognostic model that integrates these complementary biomarker inputs to overcome the limitations of single-analyte approaches and achieve more robust risk stratification. Methods: A high-throughput microfluidic platform was developed for label-free blood plasma separation without external force fields such as magnetic separation or centrifugation. The device was characterized across flow rates of 650–1450 µL/min using whole blood at varying dilution factors, with plasma yield and purity evaluated at each condition. The separated plasma fraction is used for downstream isolation of tEVs and ctDNA, while the cellular fraction is used for CTC enrichment. CTCs are identified and enumerated via immunofluorescence staining. ctDNA is detected by dPCR, with size profile and concentration further characterized. EVs are assessed by Western blot for pancreatic cancer-associated marker expression, and nanoparticle tracking analysis is used to quantify concentration and size distribution. Results: Our plasma separation microfluidic platform achieves ∼99% separation efficiency and 6.5% plasma yield using 4-fold diluted blood at 1,450 µL/min — a throughput three-fold higher than the highest previously reported in the literature. From the same blood draw, CTC enumeration is performed; ctDNA fragmentation profile, concentration, and KRAS mutation status are analyzed; and tEV size distribution, concentration, and proteomic markers are characterized. These multimodal features will be integrated as inputs for a longitudinal machine learning model for pancreatic cancer risk stratification. Conclusion: Our platform demonstrates the feasibility of an integrated multi-analyte liquid biopsy workflow from a single blood draw. The long-term goal is to leverage tumor-specific information at the genomic, transcriptomic, and proteomic levels to construct a robust machine learning model for longitudinal tumor monitoring, ultimately enabling more informed clinical decision-making for pancreatic cancer patients. Citation Format: Yu-Shu Cheng, Yin Zou, Ashleigh Montle, Shamileh Fouladdel, Anders Bogard, Nicole Peterson, Va","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"99 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048819","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 A137: Chemotherapy utilization and outcomes in patients with metastatic pancreatic adenocarcinoma","authors":"Shubham Pant, Pranoti Pradhan, Yuexi Wang, Aliza R. Karpes Matusevich, Ziyu Lan, Brandon Kent, Clay Gustafson, John Graham, Preeti S. Bajaj","doi":"10.1158/1538-7445.pancreatic26-a137","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a137","url":null,"abstract":"Background: Metastatic pancreatic adenocarcinoma (mPDAC) is associated with poor prognosis and limited treatment options. While guidelines recommend chemotherapy (CTx) for patients with good performance status (PS), many patients do not receive CTx or discontinue shortly after initiation. Non-treatment is often attributed to poor PS, comorbidities, or organ dysfunction; however, treatment-related factors including toxicity burden and limited effectiveness of available CTx options may also contribute. This study aimed to understand characteristics and outcomes of patients with de novo mPDAC who do not receive or are intolerant to CTx. Methods: This study used ConcertAI Patient360™ electronic health records with linked claims. Adult patients were included if they were diagnosed with de novo mPDAC between 1/2020–3/2025 and had >3 months of follow-up unless censored due to death. Patients were categorized into 3 cohorts: CTx-untreated, CTx-tolerant (initiated and continued CTx for >90 days unless due to progression), and CTx-intolerant (initiated CTx within 90 days of diagnosis but discontinued within 90 days without evidence of progression or re-treatment). Demographics, clinical characteristics, overall survival (OS), and resource utilization were evaluated. Results: Of the 2708 patients meeting eligibility criteria, 953 (35%) were CTx-untreated. A total of 1635 initiated treatment within 90 days; 1105 (41%) were classified as CTx-tolerant and 530 (20%) as CTx-intolerant. CTx-untreated patients tended to be older and had worse PS. CTx-intolerant patients were slightly older and had worse PS than CTx-tolerant patients. Median OS was 1.74 months in CTx-untreated, 11.37 months in CTx-tolerant, and 2.63 months in CTx-intolerant patients. CTx-untreated and CTx-intolerant patients had higher resource utilization per patient per month. Conclusions: In a large cohort of patients with de novo mPDAC, more than half of patients were untreated or unable to tolerate CTx, possibly related to older age and worse PS. Survival was substantially shorter and resource utilization higher in these groups than among those who received and tolerated CTx. While CTx demonstrates improved outcomes among those who receive and tolerate it, these findings also highlight a significant need for improved treatment options for mPDAC. Citation Format: Shubham Pant, Pranoti Pradhan, Yuexi Wang, Aliza R. Karpes Matusevich, Ziyu Lan, Brandon Kent, Clay Gustafson, John Graham, Preeti S. Bajaj. Chemotherapy utilization and outcomes in patients with metastatic pancreatic 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 A137.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"19 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048820","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 B112: Mast cell cross-talk with primary and metastatic pancreatic tumor cells","authors":"Natalia Ramirez-Sotelo, Reegan Miller, Damian P. Matysniak, Kamiya Mehla","doi":"10.1158/1538-7445.pancreatic26-b112","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b112","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC), notorious for its fatality, claims a five-year survival rate of around 13%. PDAC is projected to become the second leading cause of cancer-related deaths by 2030. PDAC is often diagnosed at the advanced stage, where the tumor has spread to distant organs such as the liver and lung. The mechanism underlying tumor cell-mediated immunosuppression at metastatic sites, which enables their successful relocation and growth, is beginning to unfold. In our project, we focused on the mast cells, which have been shown to promote pancreatic tumor growth by aiding in angiogenesis and immunosuppression (via IL-10 secretion). However, the role of these cells in lung metastasis in pancreatic cancer remains unknown. Thus, we first assessed how the crosstalk between mast cells and primary and metastatic pancreatic tumor cells varies by performing in vitro co-culture experiments (1:1 ratio with cell culture inserts). We examined the impact of primary and metastatic pancreatic tumor cells on mast cells by performing bulk RNA sequencing and LC-MS/MS metabolomic analyses. In parallel, we also harvested tumor cells from these co-culture cohorts and performed bulk RNA sequencing to assess the effect of mast cells on tumor cells. For our mast cell model, we used MC/9 cells, an IL-3-dependent cloned mast cell line derived from mouse fetal liver. For co-culture studies, we used KPC1245 and KPC242 (primary pancreatic tumor cell lines) and a KPC242-derived lung metastatic cell line. Our data showed that both primary and metastatic cells significantly increased the expression of inflammatory mediators such as IL-13, IL-6, and tryptase in mast cells upon co-culture. Also, LC-MS/MS analyses showed significant alterations in the arginine and phenylalanine metabolic pathways in mast cells upon culture with primary or metastatic pancreatic tumor cell lines compared to the cultured-alone cohort. Notably, we also observed a concurrent increase in IL-13 receptor (IL-13ra1) expression on co-cultured pancreatic tumor cells, suggesting a possible crosstalk between these cells via the IL-13-IL-13 receptor signaling axis. Importantly, we observed a marked increase in several hypoxia-associated genes, including Adrenomedullin (Adm), Colony Stimulating Factor 2 Receptor Subunit Beta (CSF2Rb), DNA-damage-induced transcript 4 (Ddit4), and basic-helix-loop-helix family member e40 (Bhlhe40), in co-cultured pancreatic tumor cells compared to cultured-alone cohorts. Notably, the expression of this hypoxia-associated gene signature was similar between co-cultured primary and metastatic pancreatic tumor cells. Overall, our data showed that there is less distinction between primary and metastatic pancreatic tumor cell-mediated transcriptomics and metabolic alteration in mast cells. In parallel, mast cells also modulate the hypoxic signatures in pancreatic tumor cells. Citation Format: Natalia Ramirez-Sotelo, Reegan Miller, Damian P. Matysniak, Kamiya Mehla. M","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"19 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048857","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 B062: Mutant Gnas confers resistance to KRAS inhibition via IL-33 in IPMN-derived PDAC","authors":"Kohki Oyama, Yuki Makino, Akiko Sagara, Bong Jun. Kim, Jimin Min, Albert Sohn, Peter Yu, Fredrik I. Thege, Anirban Maitra","doi":"10.1158/1538-7445.pancreatic26-b062","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b062","url":null,"abstract":"Background: Oncogenic mutations in KRAS and GNAS are major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), precursor lesions of pancreatic ductal adenocarcinoma (PDAC). We previously showed that pancreas-specific co-expression of Kras G12D and Gnas R201C in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-Gnas R201C) mice (“Kras;Gnas” mice) generates cystic lesions that recapitulate human IPMNs. Here, we investigated the mechanisms of resistance to KRAS inhibition in Kras;Gnas-driven IPMN/PDAC. Methods: Cell lines derived from murine Kras;Gnas-driven IPMN/PDAC tumors were used to assess sensitivity to MRTX1133 and RMC6236 by cell viability assays. Because IL-33 is markedly upregulated following doxycycline (Dox) -induced expression of mutant Gnas, we examined whether IL-33 knockout alters response to KRAS inhibition. Allograft transplantation models were used to evaluate the effects of mutant Gnas and IL-33 on sensitivity to MRTX1133 in vivo. For mechanistic analyses, we performed bulk RNA-seq of Kras;Gnas cells and scRNA-seq of pancreatic tissues from Kras;Gnas IL-33 WT and KO mice. Results: Dox-induced expression of mutant Gnas rendered Kras;Gnas cells less sensitive to MRTX1133 and RMC6236 than cells under Dox-negative condition. This effect was completely abolished by IL-33 knockout. In vivo, transplanted tumors in mice fed a normal diet showed significant regression following MRTX1133 treatment, whereas tumors in Dox-fed mice failed to respond, indicating that mutant Gnas confers resistance to KRAS inhibition. Notably, IL-33-deficient tumors regressed significantly even under Dox-fed conditions, demonstrating that IL-33 is required for mutant Gnas-mediated resistance. Transcriptomic analyses revealed that mutant Gnas promotes a shift toward a classical PDAC phenotype with reduced dependence on KRAS–MAPK signaling, providing a mechanistic basis for the altered drug response. Conclusion: Mutant Gnas reduces sensitivity to KRAS inhibition, at least in part, through IL33 and by promoting a shift toward a KRAS-MAPK-independent and classical PDAC phenotype. These findings identify IL-33 as a key mediator of resistance and a potential therapeutic target for enhancing the efficacy of KRAS-targeted therapies in pancreatic neoplasms. Citation Format: Kohki Oyama, Yuki Makino, Akiko Sagara, Bong Jun. Kim, Jimin Min, Albert Sohn, Peter Yu, Fredrik I. Thege, Anirban Maitra. Mutant Gnas confers resistance to KRAS inhibition via IL-33 in IPMN-derived PDAC [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 B062.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"65 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048603","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 B014: Leveraging dynamic epigenetic landscapes to decode tumor-associated macrophages in pancreatic ductal adenocarcinoma","authors":"Debbie K. Ledezma, Kevin Gulay, Hervé Tiriac, Andrew M. Lowy, Christopher K. Glass","doi":"10.1158/1538-7445.pancreatic26-b014","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b014","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with 90% of patients developing resistance to standard chemotherapy, such as gemcitabine/paclitaxel protein-bound (GnP). PDAC tumors are characteristically immunosuppressive and fibrotic due to programs activated in tumor-associated macrophages (TAMs) and their crosstalk with cancer-associated fibroblasts. These harsh tumor conditions contribute to the therapeutic resistance observed in patients. Preclinical studies demonstrate blockade of signaling pathways in PDAC TAMs can induce macrophage reprogramming to support antitumor response and restore chemosensitivity in tumors. Yet, their translation to the clinic has had minimal benefit in improving patient survival, particularly due to the persistence of macrophage reprogramming. If the PDAC microenvironment is to be effectively remodeled by altering TAM functionality to improve therapeutic outcomes, it is critical to understand the upstream, epigenetic regulatory mechanisms driving these different PDAC macrophages states that enable tumor progression and chemoresistance. Our work into tissue macrophages has demonstrated the transcription factor MITF strongly regulates how macrophages respond to environmental signals. Specifically, MITF binding to gene enhancers, which are DNA regions that instruct when genes are expressed, is upregulated, leading to activation of MITF-dependent genes, which are found among immunosuppressive macrophage programs. Leveraging the MITF-dependent gene signature activated in macrophages, we sought to address how MITF-associated enhancers are mechanistically influencing PDAC TAM functions as the tumor becomes more advanced and develops chemoresistance. The MITF-dependent gene signature is enriched in TAM subsets from both human PDAC and PDAC tumors from KPC (Kras +/LSL-G12D;Trp53 +/LSL-R172H;Pdx1-Cre) mice, suggesting that in part, PDAC TAMs may depend on MITF-associated enhancers. We are now processing murine parental and GnP chemotherapy-resistant tumors through a single-nuclei paired-tag omics approach to simultaneously evaluate gene expression and histone modification H3K27ac at the single cell level. This work will provide a multi-omics view of the epigenetic landscape in therapy-resistant PDAC, which will be critical to identify relevant MITF-associated enhancers that are modulated in TAMs during resistance prior to in vivo validation. Overall, our data will inform how epigenetic mechanisms are directly linked to establishing different TAM states in PDAC to facilitate novel therapeutic targets that can remodel the PDAC microenvironment and improve response to existing therapies. Citation Format: Debbie K. Ledezma, Kevin Gulay, Hervé Tiriac, Andrew M. Lowy, Christopher K. Glass. Leveraging dynamic epigenetic landscapes to decode tumor-associated macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Ther","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048640","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 B117: From Epitranscriptomic to Metabolic Switch: PCIF1-Driven m6Am Modification Rewires Macrophage Lactate Metabolism to Orchestrate the Pancreatic Cancer Immune Microenvironment","authors":"Qing Wang, Tianshu Liu","doi":"10.1158/1538-7445.pancreatic26-b117","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b117","url":null,"abstract":"Pancreatic cancer (PC) remains resistant to immune checkpoint inhibitors (ICIs) due to its profoundly immunosuppressive tumor microenvironment (TME), where tumor-associated macrophages (TAMs) predominantly adopt M2-like phenotypes. N6,2'-O-dimethyladenosine (m6Am) is a dynamic RNA modification at the messenger RNA (mRNA) cap structure, and phosphorylated CTD-interacting factor 1 (PCIF1, also known as CAPAM) is its sole methyltransferase. We first analyzed PCIF1 expression in PC patients from public single-cell RNA sequencing (scRNA-seq) datasets. We then generated a myeloid-specific Pcif1 knockout mouse model (Pcif1fl/fl; Lyz2Cre, termed Pcif1-MKO) and established Panc02 orthotopic and subcutaneous PC models. Tumor growth, immune infiltration, and macrophage polarization were assessed by flow cytometry, and mass cytometry (CyTOF) . m6Am sequencing (m6Am-seq) and ribosome profiling (Ribo-seq) were combined to identify PCIF1 targets. Extracellular acidification rate (ECAR) was measured by Seahorse XF analysis. We found that PCIF1 was highly expressed in PC patient CD14+/macrophage cells and correlated with poor response to PD-1 blockade. Myeloid-specific Pcif1 deletion significantly suppressed Panc02 tumor growth, increased M1 macrophage infiltration (F4/80+CD86+), and enhanced CD8+ T cell effector function. Mechanistically, PCIF1 catalyzed m6Am modification on malic enzyme 1 (ME1) mRNA, suppressing its translation efficiency. PCIF1 loss elevated ME1 protein, increased lactate production, and promoted M1 polarization. Conversely, PCIF1 overexpression reduced lactate accumulation, which relieved P60-mediated selective autophagic degradation of SOCS3, thereby suppressing M1 polarization and promoting immune escape. These findings establish a novel \"RNA epigenetics–metabolism–autophagy\" axis in which PCIF1/m6Am/ME1 signaling reprograms macrophage lactate metabolism to control SOCS3 stability and dictate M1/M2 polarization. Targeting PCIF1 or ME1 represents a promising strategy to reverse immunosuppression and enhance ICI efficacy in pancreatic cancer. This abstract was written with assistance from generative artificial intelligence. Citation Format: Qing Wang, Tianshu Liu. From Epitranscriptomic to Metabolic Switch: PCIF1-Driven m6Am Modification Rewires Macrophage Lactate Metabolism to Orchestrate the Pancreatic Cancer Immune Microenvironment [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 B117.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048666","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 B116: Myeloid cell co-activation via Dectin-1 and CD40 agonists coordinates non-classical mechanisms of T cell cytotoxicity in Pancreatic Ductal Adenocarcinoma","authors":"Anna S. Thickens, Kelly Markowitz, Heather Coho, John McVey, Isabella Vitales, Sherry Kong, Yan Li, Devora Delman, Gregory Beatty","doi":"10.1158/1538-7445.pancreatic26-b116","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b116","url":null,"abstract":"Immunotherapy efficacy in pancreatic ductal adenocarcinoma (PDA) remains limited due to immune evasion mechanisms like MHCI downregulation which impair T cell–based responses. Strategies engaging alternative cytotoxic pathways are needed to overcome such resistance. We previously demonstrated that coactivation of myeloid cells by targeting the pattern recognition receptor Dectin-1 and activating receptor CD40 drives T cell infiltration into tumors and durable tumor regressions in PDA mouse models. Although CD8+ T cells were necessary for tumor regressions, neither MHCI expression by tumor cells nor perforin were required. Here, we investigated the Fas/Fas-ligand (FasL) axis activated by Dectin-1/CD40 coactivation. Mice were subcutaneously implanted with KPC PDA tumors and treated 14 days later with an injection of Dectin-1 (odetiglucan) and CD40 agonist (FGK45), followed by blocking antibodies every 3 days for 14 days. We found increased frequencies of FasL+ CD8+ T cells in the peripheral blood 7 days after coactivation via flow cytometry (control mean 13.3% CD8+ cells, coactivation 32.5%, p=0.038). Further, scRNAseq revealed a 113% increase in mean Fasl expression by tumor infiltrating CD8+ T cells. IHC demonstrated increased Fas expression on tumor cells after coactivation. This increased Fas expression was partially dependent on IFNg, as aIFNg reduced Fas expression, though not to control levels (mean control Fas+ 2.4% of CK19+ area, coactivation 24.3%, coactivation + aIFNg 10.53%, control vs coactivation p=0.003, coactivation +/- aIFNg p=0.004). In vitro assays demonstrated that the highest levels of Fas expression on PDA cells were induced by the combination of IFNg and IL1B (Fas MFI control 120.9, IL1B 123.2, IFNg 198, IL1B + IFNg 332.3). Notably, scRNAseq revealed a 29.8% increase in mean Il1b expression by tumor macrophages after coactivation, suggesting a role for activated macrophages in sensitizing tumor cells to Fas-induced cell death. FasL blockade abrogated the survival benefit of coactivation therapy in MHCI-knockout tumors (median survival: control 26 days, coactivation undefined, coactivation + aFasL 28 days; control vs coactivation p=0.024, coactivation vs coactivation + aFasL p=0.049). In MHCI-competent tumors, aFasL impaired tumor regressions, as percent change in tumor volume between day 33 and day 0 post-treatment was higher with aFasL (coactivation mean tumor volume percent change -90.86, coactivation + aFasL 61.84, p=0.049). While coactivation therapy induced durable antitumor memory that allowed rejection of an MHCI-knockout tumor rechallenge, FasL blockade during rechallenge impaired this memory response and significantly shortened survival (naïve control median survival 41 days post-tumor implantation, rechallenge control undefined, rechallenge + aFasL 66 days; rechallenge +/- aFasL p=0.005). These studies demonstrate that Dectin-1/CD40 coactivation overcomes PDA immune evasion by engaging FasL-dependent pathways of T c","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048667","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 B119: Generation of an Endogenous PDAC-Specific TCR Transgenic Mouse","authors":"Chong Zuo, Li Qiang, Madeline Fitzgibbon, Stephanie K. Dougan, Michael L. Dougan","doi":"10.1158/1538-7445.pancreatic26-b119","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b119","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and remains largely refractory to chemotherapy and immunotherapy. Although KRAS inhibitors show promising initial efficacy, resistance rapidly emerges, and immunotherapy responses are mostly restricted to the rare subset of patients with microsatellite instability-high tumors. Together, these findings underscore the potential of immune-based strategies, while highlighting our incomplete understanding of the immune regulatory mechanisms in pancreatic cancer. Using orthotopically implanted KPCY (6694c2) tumors, we have demonstrated that a stabilized IL-21 variant (21h10) combined with the KRAS inhibitor MRTX1133 cured resistant PDAC through a CD4+ T cell–dependent, but CD8+ T cell–independent, mechanism. Using single cell TCR clonotype tracking from mice treated with combination 21h10 and MRTX1133, we identified clonally expanded Th1-polarized CD4+ T cells that we hypothesized were responding to tumor antigens. TCRs derived from these expanded CD4 T cell populations were cloned and expressed in 58α-/-β-/- T cells for antigen screening, leading to the identification of two tumor-specific CD4+ TCRs, TCR33 and TCR125. These TCRs recognize an endogenous PDAC antigen shared across KPC cell lines and do not recognize Cre recombinase or YFP. We subsequently generated a TCR33 transgenic mouse and confirmed the development of TCR33-expressing CD4+ T cells on a RAG2-/- background. This model will enable mechanistic studies of antigen-specific CD4+ T cell–mediated tumor control and immune regulation in PDAC. Citation Format: Chong Zuo, Li Qiang, Madeline Fitzgibbon, Stephanie K. Dougan, Michael L. Dougan. Generation of an Endogenous PDAC-Specific TCR Transgenic Mouse [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 B119.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048669","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 PR015: Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression","authors":"Despoina Kalfakakou, Sungsik Kim, Lidong Wang, Qi Su, Daniel C. Cameron, Emily A. Kawaler, Motoyuki Tsuda, Elektra Manolakos, Xiaohong Jing, Cristina Hajdu, Dylan L. Tamayo, Yoona Shim, Amanda Ackermann, Daniel Weissinger, Hayley Zimny, Rosmel Hernandez, Matthew Beier, Dacia Dimartino, Peter Meyn, Kalina Rice, Shanmugapriya Selvaraj, Cynthia Loomis, Adriana Heguy, Amanda W. Lund, Hannah Carter, Rosalie C. Sears, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M. Simeone","doi":"10.1158/1538-7445.pancreatic26-pr015","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-pr015","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand how this heterogeneity contributes to PDAC biology, we analyzed a large cohort of primary tumors (n=62) profiled by scRNA-seq (443,451 single cells), including a subset of 11 tumors with matched spatial transcriptomics (53,236 spots), to map clonal, transcriptional, and spatial diversity. Moreover, our sample set includes a unique cohort of matched samples from six tumors collected before and after treatment with chemotherapy. To understand the contribution of this heterogeneity to PDAC biology, we analyzed a large primary PDAC cohort with matched single-cell and spatial transcriptomics methods (n=62), profiling 443,451 single cells and 53,236 spatial spots to map clonal, transcriptional, and spatial diversity. Our analysis revealed significant intratumoral heterogeneity, with multiple genetically distinct neoplastic clones co-existing within individual tumors. We also detected whole genome duplication (WGD) patterns in each sample by comparing the distribution of total UMI counts in malignant clones to those of non-malignant epithelial cells. Across all tumors, WGD was identified in 32.6% of samples, consistent with reported frequencies. We observed clone-specific ligand–receptor programs that are modulated by genomic dosage: amplifications of ligands or receptors enriched corresponding interactions, while deletions suppressed them, with; these genetically encoded differences were supported by spatial transcriptomics and multiplex immunofluorescence. Phylogenetic integration identified focal 8q24 (MYC) amplification as recurrently associated with classical-to-basal transitions occurring within tumor lineages at a frequency above chance; these transitions were accompanied by coordinated depletion of immune-response programs. Functional perturbation experiments in murine and primary human models showed that MYC knockdown reactivates classical transcriptional programs (GATA6, CDH1, FOXA2, MUC1, EPCAM) and restores immune-response pathways (MHC class I/II and B2M), supporting a role for MYC in maintaining a basal, immune-depleted state. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones tended to shift toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity, and TME interactions in shaping human PDAC biology. This work provides new insights into a detailed view of the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis. Citation Format: Des","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048720","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 A050: NEIL2 regulates RNA polymerase II dynamics to suppress transcription–replication conflicts in pancreatic cancer","authors":"Fan Meng, Tony Fernandez, Changfei Luan, Marc Attiyeh, Qianhua Feng, Alexander Lee, Haihua Feng, Tiane Li, Tingting Zhou, Yun Li, Rockne Russel, Terence Williams, David Dawson, Binghui Shen, Jen Jen Yeh, Yilun Liu, Maria Ninova, Mustafa Raoof","doi":"10.1158/1538-7445.pancreatic26-a050","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a050","url":null,"abstract":"Background: Transcription–replication conflicts (TRCs), arising from spatiotemporal interference between transcription and replication machinery, are major sources of genome instability in cell. In pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS promotes TRC formation, and pharmacological exacerbation of endogenous TRCs exhibits antitumor activity. However, the clinical significance and regulatory mechanisms of TRCs in PDAC remain poorly understood. Here, we identify Nei-like DNA glycosylase 2 (NEIL2), a bifunctional DNA glycosylase involved in transcription-coupled base excision repair (TC-BER), as an essential suppressor of TRCs through regulation of RNA polymerase II (RNAPII) dynamics in PADC cells. Methods: TRCs were quantified in human PDAC tissue microarrays (TMAs) and pancreatic cell models using proximity ligation assays (PLA). Mechanistic studies were performed in CRISPR/Cas9-mediated NEIL2 knockout (N2KO) and siRNA-mediated knockdown models using immunostaining, DNA fiber assays, flow cytometry, real-time cell analysis (RTCA), genomic analyses, R-loop profiling, RNA polymerase II (RNAPII) chromatin immunoprecipitation sequencing (ChIP-seq), and co-immunoprecipitation (Co-IP)-based proteomics. Results: Using PLA-based TRC detection in patient samples, we provide direct evidence that TRCs are enriched in tumor cells relative to stroma and adjacent normal ductal epithelium. TRCs positively correlate with tumor size, and grade. We orthogonally validate the critical role of NEIL2 in regulating TRCs using CRISPR-mediated gene knockout. Mechanistically, we found that NEIL2-regulates TRCs independent of its DNA binding domain which is critical for aberrant base detection in BER. Loss of NEIL2 results in aberrant RNAPII occupancy at both the transcription start (TSS) and end sites (TES) through unique mechanisms, collectively promoting TRC formation and DNA damage. Functionally, Loss of NEIL2 selectively impairs PDAC cell viability and proliferation in both 2D and 3D in-vitro models but has no effect on normal cells. Collectively, our study defines an essential non-canonical and adaptive function of NEIL2 in mitigating TRCs in PDAC. Conclusions: Our findings establish TRCs as clinically relevant features of PDAC and identify NEIL2 as a critical regulator of TRC suppression and RNAPII dynamics. These results uncover a novel oncogenic role for NEIL2 and support therapeutic targeting of NEIL2 and TRCs in PDAC. Citation Format: Fan Meng, Tony Fernandez, Changfei Luan, Marc Attiyeh, Qianhua Feng, Alexander Lee, Haihua Feng, Tiane Li, Tingting Zhou, Yun Li, Rockne Russel, Terence Williams, David Dawson, Binghui Shen, Jen Jen Yeh, Yilun Liu, Maria Ninova, Mustafa Raoof. NEIL2 regulates RNA polymerase II dynamics to suppress transcription–replication conflicts 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. Philadelp","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":"149048752","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}