tbuckley/cabot-search huggingface dataset:
Abstract B082: Extinction of oncogenic <i>Kras</i> in genetic mouse models eradicates pancreatic cancer by inducing Fas-dependent apoptosis by CD8+ T cells
Authors: Valerie S. LeBleu, Krishnan K. Mahadevan, Elena V. Ramirez, Yang Chen, Bingrui Li, Amari M. Sockwell, Mihai Gagea, Hikaru Sugimoto, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K. Jain, Ronald A. DePinho, Aniban Maitra, Kathleen M. McAndrews, Raghu Kalluri
Journal: Cancer Research (2024)

Abstract Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional extinction of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* extinction recruits CD4+ and CD8+ T cells, promotes the activation of putative antigen presenting CD11b−CD11c+ dendritic cells, and suppresses CD11b+ myeloid cell infiltration. Our findings shows that Kras* drives T cell suppression in PDAC. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the death receptor Fas in cancer cells, via repression of its promoter region mediated by functional recruitment of DNA methyltransferase 1 (DNMT1), trimethylation of histone 3 at lysine 27 (H3K27me3), the histone methyltransferase EZH2, and suppression of acetylation of histone 3 at lysine 27 (H3K27ac). Further, analysis of human RNA sequencing reveals that Kras* expression levels inversely correlate with FAS expression and PDAC tumors with high KRAS demonstrate low CD8+ T cell infiltration, which is associated with shorter overall survival in PDAC patients. Given that specific and effective targeting of Kras* results in the CD8+ T cell mediated, Fas dependent apoptosis of cancer cells and eradication of PDAC in mice, this study highlights the direct role of Kras* in suppression of tumor immunity and supports a role for immunotherapy in combination with Kras* targeting strategies to control PDAC. Citation Format: Valerie S. LeBleu, Krishnan K. Mahadevan, Elena V. Ramirez, Yang Chen, Bingrui Li, Amari M. Sockwell, Mihai Gagea, Hikaru Sugimoto, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K. Jain, Ronald A. DePinho, Aniban Maitra, Kathleen M. McAndrews, Raghu Kalluri. Extinction of oncogenic Kras in genetic mouse models eradicates pancreatic cancer by inducing Fas-dependent apoptosis by CD8+ T cells [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 B082.
Abstract C082: Decoding the KRAS-dependent proteome through the ribosomal lens
Authors: Kamini Singh, Trang Uyen Nguyen, Eric Nels Pederson, Vinay Kumar, Xiaoling Yun, Zhengqing Ouyang
Journal: Cancer Research (2024)

Abstract Our study addresses the gap in understanding the KRAS-specific translation landscape and functional proteome in cancer. We demonstrate that mutant KRAS drives distinct mechanisms of translational control to fuel cancer growth. By leveraging ribosome footprinting and advanced sequencing techniques, we investigate the impact of sotorasib, a targeted inhibitor of G12C mutant KRAS activity, on translation. Notably, KRAS (G12C) inhibition profoundly alters the translation of ribosomal proteins and translation elongation factors. Additionally, we reveal that KRAS inhibition resulted in ribosome stalling on a specific subset of mRNAs. Acute treatment with sotorasib hampers the translation of crucial oncogenic proteins, including MYC, as well as proteins involved in metabolism. These translational changes are facilitated by specific RNA motifs and RNA binding proteins that respond to KRAS activity. In essence, our study delineates the KRAS (G12C)-specific regulation of translation and elucidates the mechanism underlying KRAS (G12C)-mediated control over the cancer proteome. Citation Format: Kamini Singh, Trang Uyen Nguyen, Eric Nels Pederson, Vinay Kumar, Xiaoling Yun, Zhengqing Ouyang. Decoding the KRAS-dependent proteome through the ribosomal lens [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 C082.
Abstract B072: SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms
Authors: Anna L. Means, Hannah Yoo, Quoc-Huy Trinh, Roshini Thiagarajan, Jinghuan Zi, Frank L. Revetta, Marcus C. Tan, Kathleen E. DelGiorno, Mary K. Washington
Journal: Cancer Research (2024)

Abstract As increasing numbers of MRIs and other scans are ordered for unrelated diseases, more and more people are being diagnosed with cystic neoplasms of the pancreas. While many or most of these will likely remain benign, intraductal papillary mucinous neoplasms (IPMNs) have a risk of progression to cancer and IPMN is now recognized as another precursor to pancreatic ductal adenocarcinoma. We are investigating the mechanisms by which IPMNs progress from benign to malignant disease in order to identify markers of progression and targets to block that progression. We found that loss of SMAD4 in conjunction with Krasmutation leads to IPMN that quickly becomes invasive in a mouse model. Examining human IPMN tissues, we found that only one in 46 benign IPMN tumors lacked detectable SMAD4 protein. Among 19 cases of invasive IPMNs, the sites of active invasion were SMAD4 negative in 7 cases, nuclear negative/cytoplasm positive in 3 cases (suggesting no active canonical signaling), and a mix of positive and negative cells in 3 cases, implicating complete or partial loss of SMAD-mediated signaling in 68% of actively invading cells. In order to understand how SMAD signaling blocks progression to invasion, we are examining cell lines from a benign mouse model of IPMN. While these lines do not have endogenous TGF beta signaling, they are capable of responding to exogenous TGF beta, suggesting that TGF beta-related ligands may be supplied by the tumor microenvironment rather than the tumor cells themselves. We are currently determining how different TGF beta family members contribute to regulation of growth and invasion in these cells. In summary, loss of the tumor suppressor SMAD4 allows an otherwise benign disease to progress to invasive cancer. Citation Format: Anna L. Means, Hannah Yoo, Quoc-Huy Trinh, Roshini Thiagarajan, Jinghuan Zi, Frank L. Revetta, Marcus C. Tan, Kathleen E. DelGiorno, Mary K. Washington. SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms [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 B072.
Abstract B061: Development of a pancreatic ductal adenocarcinoma 3D tumor model for high-throughput drug screening
Authors: Xiaoyu Song, Yuma Nihashi, Yasuyuki S. Kida
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a persistent malignancy that is difficult to diagnose in its early stage and is one of the leading cancer-related deaths worldwide. Currently, limited therapeutic options are available for PDAC, resulting in an extremely low 5-year survival rate. To speed up the discovery of novel therapeutics, a reliable 3D model that highly simulates the PDAC tumor microenvironment is needed for large-scale drug screening. In this study, we propose a novel 3D model for restoring the PDAC tumor microenvironment by targeting cancer-associated fibroblasts (CAFs), which serve as the key component of the PDAC, providing its heterogeneity and contributing to reciprocal signaling and drug resistance. Our previous studies have demonstrated that Adipose-derived mesenchymal stem cells can differentiate into varying subtypes CAFs when co-cultured with PDAC cells both in vitro and in vivo. Following this strategy, we utilize the fibroblast-populated collagen lattice (FPCL) modeling approach, which relies on the contractility of fibroblasts in a collagen gel matrix, to provide the mechanical stress and hypoxic conditions for the 3D tumor models. Human Adipose-derived mesenchymal stem cells as CAF precursors and PDAC cell lines were mixed with collagen solution to make the collagen discs, resulting in the formation of 3D PDAC tumor models within a week. The morphological analyses, along with global transcriptome and metabolomic analyses, were performed to confirm the clinical-like mature ductal glands of PDAC cells and CAFs-like spindle-shaped of mesenchymal stem cells in the interior of PDAC-FPCL (PDAC-F). Moreover, the PDAC-F has shown a high tumorigenic potential in vivo animal model. Additionally, PDAC-F was shown to allow combination therapies screening of anticancer and antifibrotic drugs in the drug screening test, demonstrating that the combination therapeutics have better efficacy. In conclusion, our PDAC-F is built with distinct features of PDAC, reproducing the heterogeneous and high stiffness with a clinical-like PDAC morphology. In addition, the short modeling time and the high reproducibility of this PDAC-F open the possibilities for large-scale drug screening, which is expected to accelerate new drug development and provide effective treatment for pancreatic cancer patients. Citation Format: Xiaoyu Song, Yuma Nihashi, Yasuyuki S. Kida. Development of a pancreatic ductal adenocarcinoma 3D tumor model for high-throughput drug screening [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 B061.
Abstract C103: Differential acquisition of extracellular lipid correlates with pancreatic cancer subtype and metastatic tropism
Authors: Gilles Rademaker, Grace A. Hernandez, Longhui Qiu, Kwun W. Wen, Aakriti Jain, Grace A. Kim, Roberto Zoncu, Rushik M. Perera
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, and the third leading cause of cancer-related death with a 5-year overall survival rate of less than 5%. Recent studies have identified two major subtypes of pancreatic cancer, basal and classical, that are predictive of patient prognosis, with basal tumors corresponding with more aggressive disease. While transcriptional signatures define basal and classical tumors and cell lines, little is known regarding the metabolic vulnerabilities linked to the basal versus classical state. Using unbiased computational interrogation to uncover metabolic genes correlating with known markers of classical PDAC, we identified high expression of Proprotein convertase subtilisin/kexin type-9 (PCSK9) – a negative regulator of receptor mediated uptake of cholesterol containing low-density lipoprotein (LDL) – as correlating with several established markers of classical PDAC. In contrast, PCSK9 expression is suppressed in Basal PDAC. Accordingly, basal PDAC uptake high levels of LDL, are sensitive to LDL depletion and show higher dependence on cholesterol uptake, relative to classical PDAC. As lipoproteins are produced in the liver, we hypothesized that basal PDAC cells may more efficiently seed and grow within the liver. Consistent with this hypothesis, low PCSK9 expression is correlated with liver metastasis in mouse models of PDAC and patient PDAC specimens. Ongoing studies will interrogate the role of PCSK9 and cholesterol uptake and utilization in metastatic tropism, and uncover unique features and vulnerabilities of the most aggressive variant of PDAC. Citation Format: Gilles Rademaker, Grace A. Hernandez, Longhui Qiu, Kwun W. Wen, Aakriti Jain, Grace A. Kim, Roberto Zoncu, Rushik M. Perera. Differential acquisition of extracellular lipid correlates with pancreatic cancer subtype and metastatic tropism [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 C103.
Abstract C016: Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma
Authors: Jacqueline B. Plesset, Heather Coho, Kelly Markowitz, Dhruv Patel, Max M. Wattenberg, Meredith L. Stone, Devora Delman, Gregory L. Beatty
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a 12.5% 5-year survival rate and is predicted to become the 2nd leading cause of cancer-related death by 2030. PDAC is known to be resistant to immunotherapy. Thus, while chimeric antigen receptor (CAR) T cell therapy shows the potential to mediate durable responses against some hematologic and solid tumors, in PDAC, the efficacy of CAR T therapy has remained limited. PDAC tumors show heterogenous T cell infiltration with some tumors containing a high number of T cells. As T cell infiltration associates with prolonged survival, we hypothesized that the density of pre-existing T cell infiltration would predict response to CAR T therapy. Methods: Previously established clonal mouse PDAC cell lines, which show a T cell inflamed or non-inflamed tumor microenvironment upon in vivo implantation, were used. Mouse CAR T cells specific to mesothelin, a tumor antigen expressed by PDAC, were generated using retroviral transduction. Mice were implanted subcutaneously with T cell inflamed or non-inflamed tumor cell lines. Ten days later mesothelin CAR T cells were administered intravenously. Flow cytometry and multiplex immunohistochemistry was used to define the density and spatial location of CAR T cell infiltration. The impact of CAR T cells on tumor growth and survival was also measured. Results: CAR T cells were found to traffic to T cell inflamed tumors, which led to delayed tumor outgrowth. However, such results were not seen in T cell non-inflamed tumors. Rather in mice with T cell non-inflamed tumors, CAR T cells accumulated in the liver. Further, CAR T cells effectively eliminated T cell inflamed and non-inflamed tumor cells in vitro, demonstrating that tumor intrinsic mechanisms of resistance to T cell killing were not a major determinant of treatment efficacy. Conclusions: Our findings suggest the therapeutic potential of CAR T cells in PDAC but highlight mechanisms of T cell exclusion as a therapeutic barrier wherein CAR T cells accumulate in host organs. Citation Format: Jacqueline B. Plesset, Heather Coho, Kelly Markowitz, Dhruv Patel, Max M. Wattenberg, Meredith L. Stone, Devora Delman, Gregory L. Beatty. Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma [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 C016.
Abstract C052: Ketogenic diet enhanced nutrient metabolic pathways but did not inhibit tumor growth in an obesity-associated PDAC mouse model
Authors: Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Fouad Choueiry, Zhu Jiangjiang, Zobeida Cruz-Monserrate
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate due to ineffective treatments. Obesity is a recognized risk factor for PDAC. Thus, developing effective weight management strategies is essential to decrease obesity, and potentially mitigate PDAC risk. The high-fat, low-carbohydrate ketogenic diet (KD) promotes weight loss and is a promising therapeutic strategy in some cancer preclinical models by altering tumor metabolism. Purpose: The KD will disrupt cancer metabolism, promote weight loss, and delay tumor growth in obesity-associated PDAC. Methods: C57BL/6 mice were fed an obesogenic high-fat diet (HFD) for 15 weeks to induce obesity, after which were randomized to a control diet (CD), a KD, or continued in the HFD for 7 weeks. After, mice were orthotopically injected with mouse KRas G12D/Trp53−/−/PDX-1-CRE (mKPC) cells containing the firefly luciferase gene. Tumor growth was monitored using luminescence through an In Vivo Imaging System. Body weight, glucose tolerance tests, and ketone measurements were performed before, during, and at the study end. Tumors metabolomics were analyzed by Liquid Chromatography Mass Spectrometry. Results: Mice gained weight after 15 weeks of an obesogenic diet. Mice that were switched to a KD or CD lost weight compared to mice that remained on the HFD following diet intervention. Mice fed a KD maintained increased ketone concentrations and increased glucose tolerance after tumors. However, none of the dietary interventions decreased tumor growth. Tumors in mice fed a KD showed significant enrichment in metabolic processes, such as, vitamin B6 and vitamin B5 metabolism, the citrate cycle, and arginine biosynthesis compared to mice that remained on a HFD. Conclusions: Although the KD induced weight loss and altered tumor metabolism, it was insufficient to decrease tumor growth in an obesogenic PDAC mouse model. Our data identified vitamin B6 and vitamin B5 metabolism, the citrate cycle, and arginine biosynthesis as important compensatory metabolic processes induced by the KD. Understanding the availability and functions of these metabolic processes could identify mechanisms of diet interventions for obesity-associated PDAC to decrease obesity, and potentially mitigate PDAC growth. Citation Format: Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Fouad Choueiry, Zhu Jiangjiang, Zobeida Cruz-Monserrate. Ketogenic diet enhanced nutrient metabolic pathways but did not inhibit tumor growth in an obesity-associated PDAC mouse model [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 C052.
Abstract B016: Eosinophils alter metastatic spread in pancreatic cancer
Authors: Megan T. Hoffman, Patrick J. Lenehan, Jen Wang, Lestat Ali, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W. Wolpin, Stephanie K. Dougan
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the US with a 11% 5-year survival rate. A key contributor of this dismal prognosis is early and frequent metastatic spread with limited treatment options for patients. Metastasis in PDA is facilitated by a robust fibroinflammatory response in the primary tumor site, a large portion of which is composed of infiltrating immune cells, and survival during transit to establish in the secondary site. In the primary tumor reactive stroma, we found increased eosinophils in both human and mouse PDA compared to the normal pancreas. Eosinophils are an innate immune cell best known for their ability to control parasite responses and have been implicated in either pro- or anti-cancer roles in various solid tumors. We used the ΔdblGata mice, which lack eosinophils, to study the role of eosinophils during metastatic spread using a resectable model of PDA metastasis. This model of metastasis was developed to facilitate consistent seeding of lung metastasis in approximately 50 percent of mice from a transient subcutaneous tumor which undergoes subsequent surgical removal and harvest to evaluate metastasis at 4 weeks. We found that mice lacking eosinophils have increased metastasis to the lung in our resectable model of PDA metastasis but no difference in establishment of IV injected PDA tumor cells, suggesting eosinophil control at the primary tumor site. Single cell sequencing of the subcutaneous tumors finds differences in the angiogenic subtypes, tip and stalk cells, in mice lacking eosinophils. Sequencing of eosinophil populations in humans and mice find an increase in angiogenic signaling suggesting a regulatory role in tumor cell access to the circulation. We conclude that eosinophils in PDA inhibit the metastatic process through control of angiogenic signaling. Citation Format: Megan T. Hoffman, Patrick J. Lenehan, Jen Wang, Lestat Ali, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W. Wolpin, Stephanie K. Dougan. Eosinophils alter metastatic spread 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 B016.
Abstract C019: The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas by reducing proteasome activity and MHC1 cell surface localization
Authors: Orjola Prela, Lan Wang, Ching-Hua Shih, Juliana Cazarin de Menezes, Brian Altman, Paula M. Vertino, Chris R. Harris, Darren R. Carpizo
Journal: Cancer Research (2024)

Abstract Many tumor types, including pancreatic adenocarcinomas, have dysregulated circadian rhythms. Here we show that the master regulator of circadian control, BMAL1, is overexpressed in pancreatic ductal adenocarcinoma (PDAC) relative to normal tissue and plays a role in protecting PDAC cells from recognition by the immune system. Using CRISPR-generated knockout (KO) cell lines, we evaluated the cells ability to create liver metastasis using a splenic metastasis assay and found that loss of Bmal1 KO abrograted metastasis. We hypothesized that could be through an immune mediated mechanism and evaluated the Bmal KO cells for their expression of cell surface MHCI. Remarkably loss of Bmal1 led to a significant increase in cell surface MHCI expression. This was due to a change in localization of the MHCI molecule. Proper localization of MHC1 is known to depend upon proteasome-generated peptides, and we found that loss of Bmal1 increased proteosomal activity. We used Cut and Run to demonstrate that Bmal1 binds directly to the promoters for core components of the proteosome. Taken together these studies implicate Bmal1 in regulating anti-tumor immunity in PDAC through its regulation of protesomal activity and MHC1 surface expression. This is a novel function for a circadian rhythm gene in PDAC biology. Citation Format: Orjola Prela, Lan Wang, Ching-Hua Shih, Juliana Cazarin de Menezes, Brian Altman, Paula M. Vertino, Chris R. Harris, Darren R. Carpizo. The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas by reducing proteasome activity and MHC1 cell surface localization [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 C019.