tbuckley/cabot-search huggingface dataset:
Abstract A053: Interrogating the spatial biology of pancreatic cancer-associated fibroblasts in resected human pancreatic cancer
Authors: Adam Bryce, Stephan Dreyer, Fieke Froeling, Silvia Martinelli, Rachel Pennie, Leah Officer-Jones, John Le Quesne, David Chang
Journal: Cancer Research (2024)

Abstract Introduction Cancer-associated fibroblasts (CAFs) are key players in the fibrotic tumour microenvironment (TME) of pancreatic cancer. Recent evidence has demonstrated the existence of multiple CAF subtypes, however there is relatively little evidence validating and corroborating these CAF subtypes in resected human pancreatic cancer. Furthermore, the spatial interactions between CAF subtypes and the epithelial and immune compartments of the pancreatic cancer TME is not well understood. Methods We designed and optimised a bespoke 8-plex immunofluorescence panel for the purposes of CAF subtype profiling and elucidation of CAF spatial biology: panCK, FAP, SMA, CTGF, S100A4, IL6, LIF, PDGFR. This was applied to a cohort of n=215 resected pancreatic cancer, well characterised with highly granular clinico-pathological and transcriptomic data through the Australian Pancreatic Cancer Genome Initiative. Spatial analysis was performed with novel computational biology techniques. Results We demonstrate seven CAF subtypes which cluster to form distinct, highly prognostic “enrichment profiles” (EPs). The cold EP represents quiescent CAFs in close proximity to immune cells (multivariate HR 0.45, 95% CI 0.30-0.68, p&amp;lt;0.001), and the fibrotic EP represents activated CAFs in close proximity to epithelial cells (multivariate HR 2.22, 95% CI 1.48-3.35, p&amp;lt;0.001). We also demonstrate the prognostic power of high spatial entropy (loss of tissue architecture, correlating with the fibrotic EP) vs low spatial entropy (preservation of tissue architecture, correlating with the cold EP) (HR 2.22, 95% CI 1.47-3.35, p&amp;lt;0.001). Conclusion We begin to unravel the elusive spatial biology of pancreatic CAFs in a large resected human cohort. We see changes in immune cell infiltrate, modulation of cellular relationships, and greater tissue disorganisation as a result of CAF activation. These features are highly prognostic and we hypothesise they are driven by changes in crosstalk between TME compartments. Current work focuses on application of these techniques to a large resected neoadjuvantly-treated cohort, allowing further interrogation of the notorious fibrotic post-neoadjuvant pancreatic cancer TME. If accepted for presentation we look forward to presenting both cohorts simultaneously. Citation Format: Adam Bryce, Stephan Dreyer, Fieke Froeling, Silvia Martinelli, Rachel Pennie, Leah Officer-Jones, John Le Quesne, David Chang. Interrogating the spatial biology of pancreatic cancer-associated fibroblasts in resected human 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 A053.
Abstract C069: A conserved reepithelialization program driven by FOSL1 underlies malignancy in pancreatic ductal adenocarcinoma
Authors: Charles David, Melian Zhuo, Yong Li, Yifeng Zhang, Chenlu Yang, Ziqing Deng, Yupei Zhao, Wennming Wu, Junya Peng, Mo Chen
Journal: Cancer Research (2024)

Abstract Benign lesions named pancreatic intraepithelial neoplasia (PanIN) are frequent in the healthy population but are precursors to deadly pancreatic ductal adenocarcinoma (PDAC). Conversion of PanINs to PDAC is poorly understood. Here we harness high resolution spatial transcriptomics to identify a core transcriptional program associated with invasive growth across human PDAC and required for PanIN-to-PDAC progression in mice. The malignancy program is lineage restricted, and predominantly comprised of transcripts activated to drive reepithelialization during skin wound healing. This wound-like program appears in rare PanIN cells that also activate tumor suppressor genes (TSGs), which keep the incipient malignant cells in check. TSG KO in PanINs leads to rapid outgrowth of the wound-like population, unleashing invasive growth, driven by the wound-induced TF FOSL1. Bidirectional interactions between malignant epithelial cells and wound-like CTHRC1-expressing CAFs enforce the malignant state. Our results suggest that wound recapitulation drives the highly invasive properties of PDAC. Citation Format: Charles David, Melian Zhuo, Yong Li, Yifeng Zhang, Chenlu Yang, Ziqing Deng, Yupei Zhao, Wennming Wu, Junya Peng, Mo Chen. A conserved reepithelialization program driven by FOSL1 underlies malignancy in pancreatic ductal adenocarcinoma [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 C069.
Abstract C076: Transcriptomic analyses of normal human pancreatic acinar cells reveal the presence of cancer subtypes that correlate with acinar ductal metaplasia
Authors: Corey M Perkins, Jinmai Jiang, Zachary Greenberg, Md Abu Talha Siddique, Linda C Williams, Jason O Brant, Kalyanne Shirlekar, Bo Han, Jamel Ali, Kristianna M Fredenburg, Kiley Graim, Diana J Wilkie, Mei He, Thomas D Schmittgen
Journal: Cancer Research (2024)

Abstract Gene expression subtypes exist in pancreatic ductal adenocarcinoma (PDAC), however comparable subtypes are not known to exist in normal human pancreas. Our laboratory has collected a large (N=55) and racially diverse (14 Black, 27 White and 14 Hispanic) cohort of normal human pancreatic acinar cell specimens that were processed at islet transplantation centers. Deceased organ donors were maintained on life support until the time the pancreas was surgically removed. Samples of primary, uncultured (Day 0) or ADM transdifferentiated (Day 6) normal pancreatic acinar cells were subjected to bulk transcriptomic sequencing. UMAP analysis of the transcriptomic data from the Day 0 samples revealed the presence of two distinguishable clusters of data that we arbitrarily refer to as Group 1 (n = 31) and Group 2 (n = 24). Heatmaps of the expression of 57 genes belonging to the exocrine-like, classical and basal subtypes produced a clear separation of the data. Since the exocrine-like genes increased in Group 1 and the basal and classical genes increased in Group 2, we refer to Group 1 as the exocrine-like subtype and Group 2 as the basal/classical subtype. The basal/classical subtype samples showed greater morphological and molecular acinar ductal metaplasia compared to those in the exocrine-like subtype. When stratified by demographics and subtype, volcano plots revealed a striking trend with Blacks, women, obese and younger individuals having significantly fewer differentially expressed genes (basal/classical vs exocrine-like) compared to Hispanics, men, nonobese and older individuals. Our data demonstrate that, similar to PDAC, normal pancreatic acinar cells are distinguishable by gene subtypes. Moreover, the gene expression ratio of these subtypes varies dramatically by donor demographics. Citation Format: Corey M Perkins, Jinmai Jiang, Zachary Greenberg, Md Abu Talha Siddique, Linda C Williams, Jason O Brant, Kalyanne Shirlekar, Bo Han, Jamel Ali, Kristianna M Fredenburg, Kiley Graim, Diana J Wilkie, Mei He, Thomas D Schmittgen. Transcriptomic analyses of normal human pancreatic acinar cells reveal the presence of cancer subtypes that correlate with acinar ductal metaplasia [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 C076.
Abstract B002: Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of <i>de novo</i> lipogenesis pathway
Authors: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is associated with one of the highest and most severe forms of cancer- associated cachexia amongst solid tumors. In an effort to further our understanding of the molecular etiology of pancreatic cancer-associated cachexia, we have developed mouse models to study adipose tissue wasting during Pancreatic Ductal Adenocarcinoma (PDAC) progression. In these pursuits, we have identified a pro-cachectic factor, PTHrP, that is produced and secreted by PDAC tumor cells and directly signals to adipocytes to facilitate wasting. Genetic deletion and pharmacological inhibition of PTHrP significantly extended the survival of tumor-bearing animals and dramatically reduced cachectic phenotypes in these animals, manifesting as decreased adipose and muscle tissue wasting. Mechanistic studies have shown crosstalk between tumor-cell derived PTHrP and adipose tissue PTH1R that drives the cachectic phenotype. Finally, bulk RNA sequencing analysis in PTHrP-driven cachectic models point towards a role for reduced de novo lipogenesis and adipogenesis in cachectic adipose depots, suggesting potential rewiring of the metabolic profile of white adipose tissue in tumor-bearing mice with higher PTHrP expression. Citation Format: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi. Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway [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 B002.
Abstract B033: MUC16 - Potential Target for Antibody-based Immunotherapy in Pancreatic Cancer
Authors: Cory L Brooks, Prakash Radhakrishnan
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most devastating and lethal cancer. PDAC patients with the current standard of care produce dismal overall survival benefits with high toxicities. Thus, there is an unmet clinical need to develop targeted therapeutics against PDAC. Approximately 50 to 70% of PDAC patients overexpress MUC16, which is associated with disease progression, metastasis, drug resistance, and poor patient survival. We demonstrated that MUC16 enhances PDAC tumor growth via binding and activating epidermal growth factor (EGF) receptor family members and its downstream target PI3K/AKT signaling pathways. Here, we show the efficacy of humanized anti-MUC16 antibody (huAR9.6) against MUC16-positive PDAC. Methods: We tested the in vitro efficacy of humanized anti-MUC16 antibody (huAR9.6) against MUC16+ PDAC cells, patient-derived xenografts (PDXs), and patient-derived organoids (PDOs). We evaluated the in vivo therapeutic efficacy of the huAR9.6 antibody in MUC16+ PDAC cells implanted in subcutaneous and orthotopic tumor models. Fucosylated and afucosylated huAR9.6 induced direct tumor-killing activity was evaluated by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with MUC16 positive PDAC cells. Results: Treatment with huAR9.6 reduced the in vitro growth, migration, invasion, and clonogenicity of MUC16+ PDAC cells and patient-derived organoids (PDOs). HuAR9.6 blocked MUC16-mediated ErbB and AKT activation in PDAC, PDOs, and PDX-derived cells. HuAR9.6 treatment induces ADCC and CDC against MUC16+ cells. Removing fucose residue on the N-glycans of the huAR9.6-IgG substantially increased huAR9.6’s ADCC activity. More importantly, huAR9.6 treatment caused PDAC regression in subcutaneous and orthotopic tumor models. Conclusion: The results of this study validate the translational therapeutic potential of huAR9.6 against MUC16-positive PDACs (detected in ∼ 50-70% of patients). Citation Format: Cory L Brooks, Prakash Radhakrishnan. MUC16 - Potential Target for Antibody-based Immunotherapy 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 B033.
Abstract C016: Pancreatitis-induced resistance to KRAS targeted therapy: The role of cellular plasticity and underlying mechanisms
Authors: Daiyong Deng, Pingping Hou
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease characterized by cell plasticity, particularly the epithelial-to-mesenchymal transition (EMT) phenotype, which significantly contributes to both pancreatic tumorigenesis and therapy resistance. Chronic pancreatitis, a key risk factor for PDAC, induces fibrosis, recruits macrophages, and elevates TGFβ, an EMT master regulator, in the tumor microenvironment (TME). Despite the observed negative correlation between dependence on oncogenic KRAS signaling and the quasi- mesenchymal (QM) subtype, the role of cellular plasticity and the underlying mechanisms of resistance remain unclear. To address this, we employed genetically engineered mouse models that mimic human pancreatitis and PDAC, alongside an in vitro 3-D tumor spheroid culture system. Our study demonstrates that chronic pancreatitis promotes resistance to KRAS- targeted therapy through a canonical TGFβ signaling pathway-dependent mechanism. Nuclear Factor of Activated T Cells 5 (NFAT5) forms a hetero-pentamer with canonical TGFβ factors SMAD3 and SMAD4, inducing EMT and promoting therapy resistance. Analysis of human samples indicates a positive correlation between NFAT5 expression and pancreatic tumorigenesis, with elevated NFAT5 expression correlating with poorer overall survival in the TCGA PDAC dataset. Functional studies reveal that genetic depletion or chemical inhibition of NFAT5 thwarts resistance to KRAS inhibition induced by TGFβ or pancreatitis, impairs the growth of QM-like escaper tumors, and synergizes with KRAS inhibitors to further suppress tumor growth in pre-clinical models. Mechanistically, we identified the chaperone protein and extracellular matrix regulator S100A4 as a key effector transcriptionally activated by the NFAT5- SMAD complex, mediating therapy resistance partially through the activation of key KRAS downstream MAPK and AKT signaling pathways. Furthermore, our investigation reveals that TGFβ stimulates PDAC cells to secrete the chemokine CCL2, which recruits circulating macrophages. In turn, these macrophages support PDAC cells in bypassing KRAS inhibition through paracrine TGFβ and S100A4. Overall, this study establishes a molecular foundation for KRAS-targeted therapy resistance associated with cellular plasticity in PDAC, highlighting pancreatitis as a potential risk factor, and proposes a novel strategy to overcome this resistance through NFAT5 inhibition or S100A4 blockade. Citation Format: Daiyong Deng, Pingping Hou. Pancreatitis-induced resistance to KRAS targeted therapy: The role of cellular plasticity and underlying mechanisms [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 C016.
Abstract B021: Development of an ultrasensitive sequencing platform for blood-based mutation profiling of pancreas cancer patients
Authors: Ryne Ramaker, James Abbruzzese, Chris Counter
Journal: Cancer Research (2024)

Abstract Introduction: One barrier to improving Pancreatic Ductal Adenocarcinoma (PDAC) patient outcomes is the absence of effective, non-invasive biomarkers for disease screening, treatment monitoring, and identification of therapeutic targets. While sequencing-based approaches to detect mutant circulating tumor DNA (ctDNA) in blood have transformed clinical management in several cancer types, use of these ‘liquid biopsies’ has lagged behind in PDAC due to low shedding of PDAC tumor cells. Nevertheless, intact circulating tumor cells have been documented in even the earliest stages of PDAC and precede the limits of disease detection on imaging or gross histology in mouse models. This suggests that circulating tumor cells could server as a PDAC biomarker if the sensitivity of sequencing could be increased. Methods: Point mutations in the gene KRAS are found in up to 95% of PDAC patients and hence represent a potential biomarker target for this cancer. To detect these pathogenic mutations in KRAS, we will adapt Maximum Depth Sequencing (MDS) for exon 2 of this gene by testing various primers and reaction conditions. The sensitivity of the K-MDS assay was optimized for blood by spiking PDAC cells with known KRAS mutations into healthy control blood at various dilutions. Finally, to evaluate the clinical sensitivity, we have collected paired blood draws from 200 advanced PDAC patients in prospective fashion, one to be tested with a commercial ctDNA test and one by K-MDS. Results: We optimized MDS to sequence exon 2 of KRAS and successfully detected a single mutant template in &amp;gt;107recovered independently barcoded templates (e.g. 107 individual KRAS alleles). We then optimized the assay for human blood and demonstrated that K-MDS could reproducibly detect a KRAS mutation corresponding to PDAC cells spiked into healthy control whole blood at the lowest dilution tested, namely one cell per ml of blood. This corresponds to a sensitivity of one mutated fragment per one million KRAS fragments, or 1000x more sensitive than currently available commercial assays. We are currently performing K-MDS on prospective PDAC cohort, with completion of this study expected this fall. Conclusions: We developed a highly sensitive sequencing assay cable of detecting PDAC ctDNA in whole blood. With successful validation in PDAC blood samples, this assay could provide a powerful tool for non-invasive PDAC mutation profiling and disease monitoring. Citation Format: Ryne Ramaker, James Abbruzzese, Chris Counter. Development of an ultrasensitive sequencing platform for blood-based mutation profiling of pancreas cancer patients [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 B021.
Abstract A012: Meta-analysis comparing the incidence of serious adverse events, overall survival, and progression-free survival in Pancreatic Adenocarcinoma patients harboring unresectable tumors treated with modified FOLFIRINOX or FOLFIRINOX regimen
Authors: Vuong Trieu, Sanjive Qazi, Seymour Fein, Anthony E Maida, Tenshang Joh, Wen-Han Chang
Journal: Cancer Research (2024)

Abstract Background. The evolution of first-line treatment for advanced pancreatic adenocarcinoma (PDAC) from Gemcitabine-based therapies to FOLFIRINOX-based regimens (fluorouracil, leucovorin, irinotecan, oxaliplatin) have demonstrated significant improvements in survival outcomes, however, this was associated with increased side effects such as neuropathy, fatigue, and diarrhea due to its heightened potency. Modified versions of FOLFIRINOX (mFOLFIRINOX) have since been developed with lower doses and longer breaks between cycles to manage side effects. Methods To systematically test the efficacy and side effects of mFOLIFINOX treatment, we conducted a meta-analysis relating FOLFIRINOX treatment with modified FOLFIROX on the frequency of Grade 3 or 4 adverse events reported in published literature (9 studies), and Serious Adverse Events (SAE) recorded from clinical trials (17 arms accessed from clinicaltrials.gov) in PDAC patients with unresectable tumors. Results For adverse events occurring in greater than 10% of patients, significant reductions in the frequency of patients experiencing the following events were observed in PDAC patients treated with mFOLFIRINOX: Neutropenia (29.31 % (226/771 patients across 8 arms) versus 18.8% (144/766 across 8 arms; Fisher Exact test, 2-tailed, P &amp;lt; 0.001)), Anorexia (18.57 % (44/237 across 3 arms) versus 5.39% (18/334 across 3 arms); P &amp;lt; 0.001), Peripheral sensory neuropathy (10.63 % (27/254 across 2 arms) versus 3.45% (4/116 across 2 arms); P = 0.025)), and Fatigue (10.57 % (83/785 across 9 arms) versus 6.77% (55/812 across 8 arms); P = 0.007)). Examination of 8 studies (N = 635) for PDAC patients treated with FOLFIRINOX exhibited a median OS time of 11.37 (Range = 10.07 - 13.9) months. Patients treated with mFOLFIRINOX (N = 475) exhibited a median OS time of 12.8 (10.2 - 14.4) months (Two-sample Wilcoxon test, P = 0.372). Conclusions In conclusion, modified FOLFIRINOX has maintained similar efficacy while reducing severe adverse events, making it more tolerable for adjuvant treatment after surgery. Citation Format: Vuong Trieu, Sanjive Qazi, Seymour Fein, Anthony E Maida, Tenshang Joh, Wen-Han Chang. Meta-analysis comparing the incidence of serious adverse events, overall survival, and progression-free survival in Pancreatic Adenocarcinoma patients harboring unresectable tumors treated with modified FOLFIRINOX or FOLFIRINOX regimen [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 A012.
Abstract C020: Identification of KRAS-specific TCRs from human peripheral blood
Authors: Jiao Shen, Blake E. Smith, Winiffer Conce Alberto, Ellen J. Kim, Michael L. Dougan, Harshabad Singh, Michael E. Birnbaum, Stephanie K. Dougan
Journal: Cancer Research (2024)

Abstract Mutant KRAS is the predominant driver oncogene in pancreatic cancer accounting for approximately 90% of KRAS mutations. However, these mutant KRAS peptides exhibit weak binding affinity to most human leukocyte antigens (HLAs), impeding their recognition by the immune system and the subsequent generation of a corresponding T cell response. Identification of KRAS-mutant specific T cells would be useful to track tumor-specific T cell responses in patients and could also be used for adoptive transfer of TCR-transduced cells. Current efforts to identify KRAS-specific T cells have been limited by their restriction to specific HLA haplotypes or the provision of only a few T cell receptor (TCR) sequences. In this study, we developed a facile means of detecting KRAS-specific T cells from peripheral blood at frequencies as low as 1 in 1,000,000. We employ an α41BB agonist-selective lentivirus system combined with a KRAS peptide pool to facilitate the high-throughput discovery of KRAS-specific TCRs in peripheral blood mononuclear cells (PBMCs) derived from both patients with pancreatic cancer and healthy donors. Through in vitro stimulation and single-cell TCR analysis, we identified a series of T cell expansions sharing the same clonotype, indicating a response to KRAS-mutant peptide stimulation. We have quantified CD4 and CD8 KRAS-specific TCRs from patients with a diverse range of HLA haplotypes. Citation Format: Jiao Shen, Blake E. Smith, Winiffer Conce Alberto, Ellen J. Kim, Michael L. Dougan, Harshabad Singh, Michael E. Birnbaum, Stephanie K. Dougan. Identification of KRAS-specific TCRs from human peripheral blood [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 C020.