tbuckley/cabot-search huggingface dataset:
Abstract A069: Study of MUC16/ERBB axis in pancreatic cancer
Authors: Amina Baniya, Michael A. (Tony) Hollingsworth
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cancer is the third leading cause of cancer-related deaths due to its poor prognosis and highly malignant nature. The altered expression of glycans and glycoproteins is associated with malignancy. MUC16 (also known as CA125) is a member of mucin family of glycoproteins known to line epithelial cells for protection and lubrication and is overexpressed in several cancer types, including pancreatic cancer, often linked with enhanced disease progression, metastasis, and reduced patient survival. Significance: Circulating levels of MUC16/CA125 has been used as a biomarker to monitor adenocarcinoma for decades. However, the functional role of CA125/MUC16 is yet to be elucidated due to a lack of studies on its large, heavily glycosylated structure and unknown functional domains. We present evidence that in addition to serving as a biomarker, circulating MUC16 has pro-tumorigenic activities. Hypothesis: Based on recent findings, we hypothesize that isoforms of MUC16 have high avidity for ErbB receptor and integrin complexes, with concomitant activation of downstream signaling cascades that include Akt and FAK, respectively. These result in the increased tumorigenic potential of pancreatic cancer cells in an autocrine manner. Experimental Design: There are four members of ErbB receptors; where receptor dimerization is a function of ligand binding and results in distinct downstream oncogenic signaling cascades. We evaluated the binding of MUC16 to different ErbB receptors, and its capacity to activate downstream signaling pathways using pancreatic cell line models that have different combinations of knock out/down of each ErbB receptor. We evaluated the global changes in the phosphorylation of oncogenic signaling molecules due to MUC16 binding using Reverse Phase Protein Array (RPPA). Results: We found that MUC16 activates Erbb4 (Y1162) along with other members of ErbB receptor family, where glycosylation of MUC16 is crucial for its biological activity. MUC16 enhanced oncogenic signaling through the phosphorylation of various downstream molecules and activated PI3K, RTK, MAPK, and DNA repair pathways. Our future directions include elucidating the molecular mechanism by which MUC16 activates the oncogenic signaling cascades via binding to ErbB receptors using our pancreatic cell line-based models. Conclusions: Understanding the biological activity of MUC16 and its cleaved product will further help in investigating the role of MUC16 in tumor microenvironment and at distant organ sites to influence the metastatic niche. Citation Format: Amina Baniya, Michael A. (Tony) Hollingsworth. Study of MUC16/ERBB axis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A069.
Abstract A033: Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33
Authors: Ajay Dixit, Paolo Provenzano, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf Brekken
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely due to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet, our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Here, analysis of human PDA single cell sequencing data revealed significant macrophage heterogeneity, with bone marrow-derived monocytes serving as the primary source for immunosuppressive TAMs. These bone marrow derived macrophages also served as a primary source of TNF-a. Deletion of Ccr2 in genetically engineered KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice decreased monocyte recruitment resulting in decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) renders PDA susceptible to checkpoint blockade therapy (CTLA-4 and PD-L1) resulting in reduced metastatic burden and increased survival in KPC mice. Additionally, TNF-a suppresses the expression of alarmin IL-33 in cancer cells, thereby hindering dendritic cell and cytotoxic T cell anti-tumor activity. When put together our data indicate that interventions to disrupt infiltration of immunosuppressive macrophages lead to decreased TNF-a, decreased metastasis and increased survival in two different models suggesting its potential role to overcome barriers to effective immunotherapeutics for PDA. Citation Format: Ajay Dixit, Paolo Provenzano, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf Brekken. Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A033.
Abstract B081: SOAT1 as a targetable KRAS dependency in PDAC
Authors: Wenjun Lan, Shoujun Sun, Jeremy Nigri, Josh Homer, Young Park, Astrid Deschenes, Paolo Cifani, Justin Cross, Victoria Gaeth, Sunny Kim, Shawn Ting, Rachel Rubino, John Moses, David Tuveson
Journal: Cancer Research (2024)

Abstract Metabolic rewiring is an emerging hallmark of neoplasia. In pancreatic ductal adenocarcinoma (PDAC), KRAS alters myriad metabolic programs to promote cellular transformation. Among them, the cholesterol synthesis pathway has emerged as a vulnerability of cancer cells due to the importance of cholesterol in membrane fluidity and the production of isoprenoid intermediates that enable KRAS membrane localization and activation in pancreatic cancer. We recently reported that the non-essential gene SOAT1 (Sterol-O-Acyl transferase 1), encoding an enzyme that esterifies free cholesterol into an insoluble form for storage and transport, is markedly upregulated in metastatic PDAC cells. SOAT1 promotes the hyperactivation of the mevalonate synthesis pathway due to loss of negative feedback by free cholesterol, thereby leading to increased production of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are required for RAS and RHO membrane localization and activity, respectively. Genetic ablation of Soat1 reduced RAS and RHO membrane localization and inhibited cellular proliferation and mitochondrial function in vitro, and these effects were largely rescued by exogenous FPP and GGPP. Therefore, our study nominated SOAT1 as a new candidate gene for therapeutic targeting. Based on SuFEx Click Chemistry (ASCC) technology, we have designed and synthesized a panel of drug-like candidates. The first series of Soat1 probes selectively impair the proliferation of PDAC cells that express SOAT1, reduce SOAT1 protein content in cells, and covalently bind to SOAT1. In mice, the most active SOAT1 probes were tolerated in a 28-day daily dosing study up to 120 mg/kg. Marked tumor growth inhibition was noted in mice bearing PDAC xenografts and GEMM mice treated as monotherapy with 15 mg/kg/d of the most active SOAT1 probe, and tissue analysis demonstrated tumor necrosis, decreased proliferation, and increased apoptosis. Mechanistically, SOAT1 loss or inhibition targets multiple important components of cellular transformation in PDAC including KRAS, RHO, and mitochondrial biology, and our work suggests that it is an attractive target to pursue for further drug development in this cancer. Citation Format: Wenjun Lan, Shoujun Sun, Jeremy Nigri, Josh Homer, Young Park, Astrid Deschenes, Paolo Cifani, Justin Cross, Victoria Gaeth, Sunny Kim, Shawn Ting, Rachel Rubino, John Moses, David Tuveson. SOAT1 as a targetable KRAS dependency in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B081.
Abstract A009: Association between unstable diabetes mellitus and risk of pancreatic cancer
Authors: Sitwat Ali, Michael Coory, Peter Donovan, Renhua Na, Nirmala Pandeya, Sallie-Anne Pearson, Katrina Spilsbury, Louise Stewart, Bridie Thompson, Karen Tuesley, Mary Waterhouse, Penelope Webb, Susan Jordan, Rachel Neale
Journal: Cancer Research (2024)

Abstract Worsening of hyperglycemia in people with pre-existing diabetes mellitus may be an indicator of undiagnosed pancreatic cancer. However, there is limited evidence from longitudinal studies regarding the association between deterioration of diabetes and pancreatic cancer in people with previously stable diabetes. The size of the association between deterioration of diabetes and pancreatic cancer, and how the association changes over time, needs further investigation. A population-based matched cohort study was conducted within Australian women with stable diabetes mellitus. Unstable diabetes, the exposure of interest, was defined as change in the type of antidiabetic medication or addition of another antidiabetic medication after at least 24 months of stable antidiabetic medication use. The date of exposure was defined as the index date. Each woman with unstable diabetes was matched to 4 women with stable diabetes by birth year (±1 year) at the index date. Flexible parametric survival models were used to estimate hazard ratios (HR) (overall and at different times) and 95% confidence intervals (CI), and absolute risk in both groups at different time points. We identified 134,954 women with unstable diabetes; these were matched to women who had not developed unstable diabetes at the index date. The mean age of the cohort was 68 years. Over a median follow-up period of 2.8 years, 1,315 pancreatic cancer cases were diagnosed. Overall, women who experienced deterioration in glycemic control had a 2.5-fold increased risk of developing pancreatic cancer (HR 2.55; 95% CI 2.29 – 2.85). The risk was very high during the initial few months [HRs at 3 months (5.76; 95% CI 4.72 – 7.04), 6 months (4.56; 95% CI 3.81 – 5.46), and 12 months (3.33; 95% CI 2.86 – 3.89)]. The risk then progressively declined with time. Worsening of glycemic control in those with previously stable diabetes may be an early clinical manifestation of pancreatic cancer. Further research is warranted to differentiate this pancreatic cancer-associated deterioration of glycemic control from other causes. The longer-term (3-7 years) weaker association between pancreatic cancer and deterioration of glycemic control suggests that poorly controlled hyperglycemia is a predisposing factor for pancreatic cancer. Citation Format: Sitwat Ali, Michael Coory, Peter Donovan, Renhua Na, Nirmala Pandeya, Sallie-Anne Pearson, Katrina Spilsbury, Louise Stewart, Bridie Thompson, Karen Tuesley, Mary Waterhouse, Penelope Webb, Susan Jordan, Rachel Neale. Association between unstable diabetes mellitus and risk of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A009.
Abstract A034: Thermoregulation alters adipose influence of pancreatic cancer growth
Authors: Austin Eades, Bailey Bye, R. McKinnon Walsh, Michael VanSaun
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States and has an abysmal 5-year overall survival of 12%. A major risk factor for PDAC is obesity- which has increased 12% between 1999-2018 in the United States. This rise correlates with the projection that PDAC is to become the second leading cause of cancer death by 2025. Clinically, reports show obese PDAC patients have a three-month decrease in overall survival when compared to lean PDAC patients. Multiple studies have implicated obese white adipose tissue (WAT) as promoting tumor progression. Yet only one study has investigated the effects of brown adipose tissue (BAT) on PDAC, which exhibited cold-mediated BAT activation steals glucose from the tumor. Aside from potential metabolic regulation, our group discovered that cold-mediated activated BAT elicited the release of anti-tumorigenic factors. We discovered this by exposing diet-induced obese mice to a subthermal environment via a thermogenic shift (TS) from thermoneutral (TN) housing. The TS BAT-conditioned media (CM) inhibited PDAC cell proliferation (EdU) and increased apoptosis (via cleaved caspase-3). Using a cytokine array, we identified endostatin as the most upregulated molecule in TS BAT-CM compared to TN BAT-CM. Incubation of PDAC cell lines with recombinant endostatin showed increased cleaved caspase-3. A shotgun-based proteomics screen uncovered novel endostatin binding partners and signaling mediators. In conclusion, we have identified a novel anti-tumorigenic role for activated BAT that further suggests its importance in relation to PDAC progression. Citation Format: Austin Eades, Bailey Bye, R. McKinnon Walsh, Michael VanSaun. Thermoregulation alters adipose influence of pancreatic cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A034.
Abstract IA13: Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer
Authors: Andrea Califano
Journal: Cancer Research (2024)

Abstract Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of regulatory protein activity in single cells identified three PDA Developmental Lineages (PDLs), coexisting in virtually all tumors, whose transcriptional states are mechanistically driven by aberrant activation of Master Regulator (MR) proteins associated with gastrointestinal lineages (GLS state), morphogen and EMT pathways (MOS state), and acinar-to-ductal metaplasia (ALS state), respectively. Each PDL is further subdivided into sub-states characterized by low vs. high MAPK pathway activity. This taxonomy was remarkably conserved across multiple cohorts, cell lines, and PDX models, and harmonized with bulk profile analyses. Cross-state plasticity and MR essentiality was confirmed by barcode-based lineage tracing, epigenetic profiling, and CRISPR/Cas9 assays, respectively. Indeed, ectopic expression of PDL-specific MRs induced transdifferentiation in vitro and in vivo. Together these data provide a mechanistic foundation for PDA heterogeneity and a roadmap for targeting PDA cellular subtypes. Citation Format: Andrea Califano. Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA13.
Abstract A023: Cytokine loss leads to decreased tumor differentiation and a more aggressive phenotype
Authors: Whitney J. Bell, Nancy Kren, Yan Wang, Jennifer Modliszewski, Yi Xu, Meijiang Guan, Kathleen DelGiorno, Jen Jen Yeh, Yuliya Pylayeva-Gupta
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of only 11% and approximately half the patients present with distant metastasis at the time of diagnosis. PDAC is accompanied by pronounced alterations in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDAC tumor evolution. The role of immune modulators in driving aggressiveness of PDAC is poorly understood. We investigate how the loss of host-derived IL-12 and IL-23 in murine models of pancreatic cancer can lead to changes in changes in tumor morphology, cellular differentiation, and tumor immune microenvironment. In orthotopic tumors isolated from IL-12 and IL-23 knockout mice tumor morphology is altered and appears to be less differentiated. Noticeably, ductal area decreases in tumors from IL-23 and IL-12 knockout mice. Single cell RNA sequencing of tumors isolated from IL-12 and IL-23 knockout mice reveals a cluster of tumor cells with decreased gastric gene expression. Gastric genes such as TFF1, TFF2, MUC5AC, GKN1, and GKN2 have been implicated in pancreatic cancer development, progression, and tumor subtype. The classical pancreatic tumor subtype designation correlates with better differentiated pancreatic tumors as opposed to the more poorly differentiated tumors in the basal subtype. The classical expression signature is characterized by the expression of GATA6 and other epithelial cell terminal differentiation genes and includes several of these gastric genes. We hypothesize that loss of IL-12 and IL-23 leads to loss of tumor differentiation and to a more aggressive phenotype. Citation Format: Whitney J. Bell, Nancy Kren, Yan Wang, Jennifer Modliszewski, Yi Xu, Meijiang Guan, Kathleen DelGiorno, Jen Jen Yeh, Yuliya Pylayeva-Gupta. Cytokine loss leads to decreased tumor differentiation and a more aggressive phenotype [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A023.
Abstract B031: Targeting epigenetic machinery to revoke stromal pro-tumorigenicity and enhance efficacy in pancreatic cancer therapy
Authors: Gaoyang Liang, Jeremiah A. Johnson, Ronald M. Evans
Journal: Cancer Research (2024)

Abstract Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) induce prominent desmoplasia in part by activating fibroblasts or their progenitors in the stroma. The resultant cancer-associated fibroblasts (CAFs) often switch on the pro-desmoplastic, pro-inflammatory and/or pro-tumorigenic transcriptional programs, contributing to tumor progression and therapeutic resistance. Identifying and targeting epigenetic machinery essential for stromal fibroblast activation provides potential strategies to revoke stromal pro-tumorigenicity and overcome therapeutic resistance in PDAC. Here we identify Class I histone deacetylases (HDACs) as key epigenetic regulators facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in stromal fibroblasts. Mechanistically, HDACs coordinate the establishment of chromatin architecture that enables the activation of pro-desmoplastic programs directed by the transcriptional factor axis of serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also facilitate the induction of pro-inflammatory program in stromal fibroblasts, supporting leukemia inhibitory factor (LIF)-mediated pro-tumorigenic crosstalk. Both HDAC depletion in CAFs and treatment of the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a novel lipogenic fibroblast subpopulation in CAFs, a potential precursor population for activated myofibroblasts in vivo. Our work pinpoints a critical role of HDACs in driving stromal pro-tumorigenicity and highlights the stromal targeting capacity of HDACi therapy. Furthermore, the clinical utility of HDACi therapy is often hindered by limited potency and nonnegligible systemic toxicity of the HDAC inhibitors. To facilitate the translation of HDACi-based therapy, we develop a polymer-based bottlebrush pro-drug (BPD) nanoparticle incorporating Ent. The Ent-BPD nanoparticle overcomes the limitations of conventional HDACi therapy by sustaining long-lasting release of HDACi activity specifically at the tumor sites. Administration of Ent-BPD in PDAC mouse models achieves superior intratumoral HDACi potency and enhanced therapeutic efficacy compared to the free drug Ent treatment; meanwhile, it avoids the systemic toxicity associated with the free drug treatment. Our work further demonstrates a promising strategy for the clinical adaptation of HDACi-based therapy. Citation Format: Gaoyang Liang, Jeremiah A. Johnson, Ronald M. Evans. Targeting epigenetic machinery to revoke stromal pro-tumorigenicity and enhance efficacy in pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B031.
Abstract A043: The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC
Authors: Yifei Guo, Jennifer M. Finan, Madeline D. Hedberg, Jonathan R. Brody, Robert Eil
Journal: Cancer Research (2024)

Abstract Immunotherapies have shown limited effectiveness in pancreatic ductal adenocarcinoma (PDAC), despite successes in many other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC through regulating key mRNA transcripts. Our lab has showed that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition and alters multiple tumor cytokine release. Thus, we hypothesized that HuR plays a role in immune evasion of PDAC. We disrupted the locus encoding HuR (Elavl1), using CRISPR Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC to assess its function in tumor immune evasion. Here, we report that HuR, a known pro-survival factor for PDAC, has a role in tumor immune evasion by suppressing T cell infiltration and T cell activation. Specifically, HuR-knockout (KO) KPC tumors grew slower compared to KPC wildtype (WT) tumors in an orthotopically implantation model (p-value&amp;lt;0.0001), even though they grew at the same rate in vitro (in a non-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells comparing to HuR-WT tumors (p-value=0.0047). Furthermore, T cell depletion partially rescued the size of HuR-KO tumors. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating the PDAC microenvironment, which therefore leads to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively active CD8+ OT-I T cells through their transgenic TCR, to measure the ability of KPC HuR-WT or HuR-KO OVA cells in directly activating CD8+ OT-I T cells. We will also rescue HuR in HuR-KO cells to validate HuR’s role in immune evasion. These findings support the concept that HuR plays an important pro-survival role of PDAC in vivo, and that targeting strategies against HuR being developed (e.g., siHuR nanotherapies and small molecule inhibitors) could potentially enhance PDAC sensitivity to immune-based anti-cancer therapies such as checkpoint blockade and T cell transfer. Citation Format: Yifei Guo, Jennifer M. Finan, Madeline D. Hedberg, Jonathan R. Brody, Robert Eil. The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A043.