tbuckley/cabot-search huggingface dataset:
Abstract PR-12: The circadian rhythm gene Dec2 regulates multiple components of the antigen presentation pathway to promote pancreatic cancer dormancy by immune evasion
Authors: Chris Harris, Crissy Dudgeon, Lan Wang, Orjola Prela, Juliana Cazarin de Menezes, Brian Altman, Brian Haab, Chongfeng Gao, Zachary Klamer, Anna Repesh, Subhajyoti De, Darren R Carpizo
Journal: Cancer Research (2024)

Abstract Metastatic recurrence following curative-intent pancreatic surgery is a major clinical problem as nearly all die of this at both early and latent periods following surgery. While latent recurrences are due to the reactivation of disseminated dormant tumor cells, the mechanisms that regulate dormancy remain unclear. Using a novel model of early-stage resectable pancreatic cancer that mimics early and latent outcomes in patients, we identified Dec2 (bhlh41) a transcriptional repressor and circadian regulator, as upregulated in dormant tumor cells harvested from the liver. Disseminated tumor cells harvest from the livers of latent recurrent mice were Dec2 hi/Ki67lo indicating that these cells are dormant. We confirmed the relationship of Dec2 and Ki67 in human pancreatic cancer using liver tissue specimens from patients with metastatic disease whereby small clusters of metastatic cells were Dec2hi/Ki67lo and larger metastatic tumors were Dec2lo/Ki67hi. To understand the mechanism of Dec2 in dormancy we deleted Dec2 from the tumor cells evaluated them in the resection model and observed a substantial increase in survival after resection due to an immune mediated mechanism as the survival benefit was abrogated in immunodeficient conditions indicating that Dec2 promotes tumor progression through immune mediated mechanism. Dec2 promotes immune evasion by downregulating multiple components of the antigen presentation pathway including proteosome and immunoproteosome genes, MHCI and MHCI chaperones. As Dec2 is a circadian regulator, we evaluated several components of the antigen presentation pathway including proteosome and surface MHCI and found these to display oscillation that was not only anti-phase with Dec2 but resulted in differential T-cell mediated tumor cell killing depending on the time of day. These studies elucidate a new mechanism by which Dec2 regulates cancer dormancy through immune evasion and identifies several novel therapeutic strategies to restore anti-tumor immunity. They also provide the first evidence that antigen presentation is under circadian regulation in pancreatic cancer. Citation Format: Chris Harris, Crissy Dudgeon, Lan Wang, Orjola Prela, Juliana Cazarin de Menezes, Brian Altman, Brian Haab, Chongfeng Gao, Zachary Klamer, Anna Repesh, Subhajyoti De, Darren R Carpizo. The circadian rhythm gene Dec2 regulates multiple components of the antigen presentation pathway to promote pancreatic cancer dormancy by immune evasion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-12.
Abstract A083: Genomic Analysis of Structural Variations in Pancreatic Cancer Using Long-Read Sequencing
Authors: Yongxing Du, Xiaohao Zheng, Yunjie Duan, Chengfeng Wang
Journal: Cancer Research (2024)

Abstract Objective: Structural variations (SVs) constitute the greatest source of genomic alterations leading to the oncogenesis of many cancers, including the deadliest pancreatic cancer (PC). However, SVs in PC remain largely undefined due to technological limitations of the traditional short-read sequencing. This study aims to establish a comprehensive signature of genomic SVs in PC. Methods: PacBio whole genome long-read sequencing was employed to investigate the genomic landscape of SVs in eight tissues from four pancreatic cancer patients. A variety of SVs callers, including pbsv, Sniffles, cuteSV, and svim, were comprehensively adopted to improve the accuracy of SVs detection. Many undefined characteristics of germline and somatic SVs were revealed by comparing with multiple previously published databases. Besides, the impacts of structural variations on 3D chromatin organization were analyzed by integrating multi-omics data including Hi-C, RNA seq and ChIP seq. Results: A total of 26,844 and 27,028 non-redundant SVs were identified in human pancreatic cancer and matched para-cancerous tissues, respectively. Notably, among these SVs, 23.97% were novel and had not been previously reported. Germline SVs were further characterized and found enriched in 25 well-known susceptible genes, such as TP63, PVT1, and ABO. Additionally, we proposed a panel of germline SVs with predicted highest pathogenicity, involving STOX1, DSPP, and WRN. Totally, 616 somatic SVs were identified and presented high burdens in patients with lymph node metastasis. We observed that somatic DELs and INSs were significantly more prevalent in repetitive regions than in non-repetitive regions. Interestingly, DELs showed a decrease in the proportion occurring in simple repeat regions but an increase in the proportion occurring in LINE and SINE regions compared to INSs. Moreover, it was observed that deletions within topologically associated domains were associated with local enhanced interactions and disrupted chromatin loops, which might influence H3K27ac modification of histone contributing to enhancer or silencer hijacking. Conclusion: This study provides insights into the genomic signature of SVs in human pancreatic cancer. These findings might shed new light on the complexity of SVs and their pathogenesis by interplaying with chromatin organization. Citation Format: Yongxing Du, Xiaohao Zheng, Yunjie Duan, Chengfeng Wang. Genomic Analysis of Structural Variations in Pancreatic Cancer Using Long-Read Sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A083.
Abstract C012: Overcoming Cell Subtype-Specific Adaptive Resistance to KRAS G12D Inhibition in KRAS G12D-Mutant Pancreatic Cancer
Authors: Qingxiang (Nick) Lin, Alvin Morales, Haley Barnes, Ryan Bruce Corcoran
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 12%, with limited treatment options. Oncogenic KRAS mutations drive PDAC tumor progression, which occur in the majority of PDAC tumors. KRAS G12D is the most common KRAS mutation, found in 36% of PDAC cases, which is associated with the worst clinical outcomes. Mutant-selective KRAS G12D inhibitors (KRASi G12D), such as MRTX1133, have recently demonstrated initial responses in KRAS G12D-mutant preclinical models. However, mechanisms of adaptive resistance to KRAS G12D inhibition are largely under-investigated and novel therapeutic strategies to overcome drug resistance are urgently needed. Results: Adaptive RAS signaling reactivation was found to dampen KRAS G12D inhibition in a library of KRAS G12D PDAC cell lines, thereby minimizing drug efficacy. Quantitative downstream analyses of drug combination screening using a KRAS G12D cell line library further identified this adaption to KRAS inhibition was cell subtype specific. Fibroblast growth factor receptor (FGFRs) drove adaptive RAS reactivation specifically in mesenchymal PDAC cells, which are aggressive, and intrinsically resistant to KRASi. In contrast, epithelial growth factor receptor (EGFR) reactivated RAS G12D signaling in epithelial cells, which are sensitive to KRASi G12D. Genetic and pharmacological inhibition of FGFR1 or FGFR2 improved drug efficacy by decreasing FGFR-mediated RAS reactivation specifically in mesenchymal PDAC lines. Pharmacological blockade of EGFR enhanced drug efficacy by inhibiting EGFR-mediated RAS reactivation specifically in epithelial PDAC lines. Furthermore, low-concentration of a novel pan- RAS inhibitor, which inhibits both wild-type and mutant RAS, completely abrogated MAPK signaling and significantly improved efficacy, when combined with KRASi G12D, suggesting a pro-survival dependency on wild-type RAS as a compensatory mechanism in response to KRAS G12D inhibition. Conclusion: Upstream RTK-mediated adaptive RAS signaling re-activation in response to KRAS inhibition in PDAC is cell subtype specific. Complete inhibition of RAS signaling by overcoming adaptive RAS rebound improves efficacy of KRASi G12D. Citation Format: Qingxiang (Nick) Lin, Alvin Morales, Haley Barnes, Ryan Bruce Corcoran. Overcoming Cell Subtype-Specific Adaptive Resistance to KRAS G12D Inhibition in KRAS G12D-Mutant Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C012.
Abstract B041: Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation
Authors: Samaneh Saberi, Cameron Bumbleburg, Caroline Everett, Julia E Lefler, Victoria Jordan, Lu Han, Sudarshana Sharma, Michael C. Ostrowski
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer distinguished by a dense stromal microenvironment. The current investigation delves into the fibroblast-specific STAT3 signaling in the PDAC tumor microenvironment (TME) and its effects on immune cell infiltration and extracellular matrix (ECM) modulation. An association was identified between heightened levels of phosphorylated STAT3 (pSTAT3) in tumor-associated fibroblasts (CAFs) and a more unfavorable prognosis, particularly among male patients. Comparative analysis of gene expression patterns in normal fibroblasts and those deficient in STAT3, extracted from mouse models of pancreatic cancer, unveiled distinct gene expression profiles related to the inflammatory signaling pathway (IL6, ADM, CXCL11, CD80, VEGFA, TGFB1, STC1, STC2). Utilizing ChIP-Seq analysis with an anti-pSTAT3 antibody, it was confirmed that STAT3 binds to the regulatory regions of these genes, supporting its regulatory role in the inflammatory signaling pathway. Moreover, the absence of STAT3 in CAFs resulted in a decline in M2 macrophages and an upsurge in M1 macrophages within the TME, indicating a potential function of STAT3 in influencing macrophage polarization. Noteworthy observations also revealed that STAT3 signaling in CAFs impacts ECM remodeling, as illustrated by reduced collagen deposition. Furthermore, the deficiency of STAT3 in CAFs led to a notable reduction in the quantity of neutrophils within the TME in our mouse model. Additionally, a plausible involvement of STAT3 in neutrophil recruitment and activation through the CXCL1/CXCR2 axis was indicated. Alterations in the infiltration of neutrophils and macrophages due to the absence of STAT3 could profoundly influence the immune response against PDAC. The modified composition of ECM following STAT3 deletion might also impact the infiltration and functioning of immune cells. These outcomes underscore the significance of STAT3 signaling in CAFs as a promising therapeutic target in PDAC, offering potential for modulating the tumor microenvironment, augmenting anti-tumor immunity, and advancing patient outcomes. Citation Format: Samaneh Saberi, Cameron Bumbleburg, Caroline Everett, Julia E Lefler, Victoria Jordan, Lu Han, Sudarshana Sharma, Michael C. Ostrowski. Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B041.
Abstract A082: Defining the lysosome proteome during pancreatic cancer tumor evolution and metastasis
Authors: Thuy T.P Nguyen, Grace A. Hernandez, Gilles Rademaker, Matthew Luy, Alexander Li, Longhui Qiu, Joao A. Paulo, Rushika M. Perera, Joseph D. Mancias
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of only 13%, characterized by rapid proliferation, high metastatic potential, and resistance to conventional therapies. PDAC tumors are heavily reliant on nutrient-scavenging pathways such as autophagy and the lysosome – a degradative organelle that plays an essential role in the digestion and recycling of diverse cellular material. Despite their importance, the specific function of lysosomes over the course of tumor evolution and metastasis in PDAC tumors remains poorly understood. To understand the function of the lysosome in PDAC, we utilize a biochemical method known as LysoIP-based proteomics, which isolates intact lysosomes for subsequent analysis using mass spectrometry-based proteomics. This approach allows for a comprehensive analysis of lysosomal composition that can uncover unique features and functions of PDAC lysosomes that promote cellular adaptation to stress in support of tumor growth. A limitation of lysosome isolation from 2D cultured cells is that it does not recapitulate lysosomal features associated with tumors growing in vivo. To address this limitation, we generated a genetically engineered mouse model of PDAC incorporating conditional expression of ‘LysoTag’ (TMEM192-mRFP-3xHA) that enables capture and profiling of lysosomes at different stages of tumor evolution, including early-stage, late-stage, and metastatic disease. Employing this strategy, we successfully captured lysosomal proteins from primary tumors (pancreas), as well as lung and liver metastases. Our preliminary analysis revealed an enrichment of resident lysosomal membrane and luminal proteins in the datasets, confirming the successful isolation of intact lysosomes from these complex tissues. Additionally, we identified non-resident lysosomal proteins (termed cargo) that are enriched and co-evolved with advancing tumor stages. Notably, our results reveal distinct differences in the lysosomal proteome of tumor cells across different tissues. These findings emphasize the critical role of lysosomal function in tumor progression and suggest that targeting lysosomal components could be a promising therapeutic strategy for treating metastatic PDAC. Citation Format: Thuy T.P Nguyen, Grace A. Hernandez, Gilles Rademaker, Matthew Luy, Alexander Li, Longhui Qiu, Joao A. Paulo, Rushika M. Perera, Joseph D. Mancias. Defining the lysosome proteome during pancreatic cancer tumor evolution and metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A082.
Abstract B060: Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening
Authors: Julia Fröse, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel R. Goulet, Michael T. Hemann
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. PDAC lacks effective treatment options and innovative strategies for therapeutic intervention are urgently needed. Chimeric Antigen Receptor (CAR)-T cell therapy has shown remarkable success in treating hematologic malignancies, yet achieving efficacy in solid tumors remains a significant challenge. Early results from clinical trials show limited efficacy of CAR T-cell therapy in PDAC. To uncover tumor-intrinsic mechanisms of resistance to CAR T-cell therapy in vivo, we performed iterative CRISPR/Cas9-based pooled screens in a fully immunocompetent, orthotopic model of PDAC. We identified a variety of genes influencing CAR T-cell treatment efficacy. In particular, loss of genes involved in redox biology and oxidative stress sensitized PDAC tumors to CAR T-cell therapy in vivo. Additionally, single-cell RNA sequencing of PDAC tumors subjected to CAR T-cell therapy unveiled a distinct subset of tumor cells resilient to the treatment, characterized by changes in oxidative stress. Our findings indicate a potential avenue for therapeutic synergy by targeting pathways involved in oxidative stress to increase the efficacy of CAR T cell therapy in PDAC. Citation Format: Julia Fröse, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel R. Goulet, Michael T. Hemann. Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B060.
Abstract C077: Functional Dissection of the Highly Plastic Basal Cell State in Pancreatic Cancer
Authors: Anupriya Singhal, Hannah C. Styers, Jonathan Rub, Zhuxuan Li, Zeynep Tarcan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Doron Betel, Yan Yan, Elisa de Stanchina, Tuomas Tammela
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Targeting cancer cell plasticity—the capacity to adapt to cell-extrinsic pressure via non-genetic mechanisms—is a promising therapeutic strategy, yet cell states within PDAC harboring high plasticity remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We identified a cancer cell differentiation state that co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. Notably, this high-plasticity cell state (HPCS) signature aligns with a "basal" signature in human PDAC, which associates with poor prognosis and chemoresistance. To functionally interrogate the HPCS in PDAC progression, we developed a novel lineage-tracing and ablation system. Lineage-tracing experiments revealed that the HPCS has a robust capacity for differentiation into epithelial and mesenchymal states, indicating that the HPCS is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the HPCS over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Further, we found that the HPCS is highly dependent on KRAS activity, with acute KRAS inhibitor treatment leading to a selective depletion of the HPCS. Taken together, our data indicates that PDAC harbors a striking dependency on the HPCS and encourages therapeutic approaches aimed at eradicating this critical subset of cancer cells. Citation Format: Anupriya Singhal, Hannah C. Styers, Jonathan Rub, Zhuxuan Li, Zeynep Tarcan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Doron Betel, Yan Yan, Elisa de Stanchina, Tuomas Tammela. Functional Dissection of the Highly Plastic Basal Cell State in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C077.
Abstract B038: Tumor Derived Parathyroid Hormone Related Protein is an Orchestrator of Immunosuppression in Pancreatic Cancer
Authors: Calvin Johnson, Jason Pitarresi
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has the lowest 5-year survival of common cancers, owing to a lack of early detection and ineffective therapies. Immune checkpoint inhibitors hold promise for PDAC patients, and while they represent the most ongoing clinical trials, they have had little success. Parathyroid Hormone Related Protein (PTHrP; encoded by PTHLH) defines the most aggressive squamous/basal/quasi-mesenchymal PDAC subtype. Our previous work revealed autocrine PTHrP signaling mediates tumor growth, epithelial-to-mesenchymal transition (EMT), and metastasis. However, PTHrP’s relationship with immune cells of the tumor microenvironment (TME) remains unknown. Investigation of tumors from KrasG12D; p53R172H; Pdx1-Cre; YFP (KPCY) and KPCY-Pthlh loxP/WT (KPCY-Pthlhhet) mice revealed less tumor associated neutrophils (TANs) and greater cytotoxic T cell infiltration, demonstrating the necessity of PTHrP for immune exclusion. Orthotopic implantation of Pthlh overexpressing KPCY cells (KPCY-PthlhOE) revealed a greater proportion of TANs than the control. A concomitant decrease in the number of effector T and natural killer cells in the KPCY-PthlhOE tumors was observed, showing PTHrP is sufficient to organize an immunosuppressive TME. Interestingly, recombinant human PTHrP was sufficient to induce TANs mobilization in vivo. To interrogate the mechanism of neutrophil trafficking into the TME, cytokine production was quantified in vitro. KPCY-PthlhOE exhibited a pronounced increase of Cxcl1 expression, a strong neutrophil chemokine, leading us to believe neutrophils migrate to the TME using a Cxcl1 gradient. Therefore, we hypothesized that PTHrP-mobilized neutrophils express the receptor for CXCL1; CXCR2. Indeed, recombinant PTHrP was sufficient to mobilize Cxcr2+ neutrophils in vivo. Furthermore, recombinant PTHrP was able to induce Cxcl1 production by KPCY tumor cells in vitro in a cAMP response element-binding protein(CREB)-dependent manner. These data describe a novel mechanism for the mobilization and infiltration of immune suppressive TANs into the TME, initiated by PTHrP. The PTHrP-dependent immunosuppressive TME excludes and inhibits effector immune cells. Further interrogation of PTHrP signaling during the genesis of the immune suppressive TME in PDAC may lead to the development of therapeutics to meet this unmet clinical need. Citation Format: Calvin Johnson, Jason Pitarresi. Tumor Derived Parathyroid Hormone Related Protein is an Orchestrator of Immunosuppression in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B038.