bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C067: Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer
Authors: Salas-Escabillas Daniel J. , Hoffman Megan T. , Brender Sydney M. , Moore Jacee S. , Wen Hui-Ju , Benitz Simone , Davis Erick T. , Long Daniel , Wombwell Allison , Steele Nina G. , Allen-Petersen Brittany , Sears Rosalie C. , Matsumoto Ichiro , DelGiorno Kathleen E. , Crawford Howard C. 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to- Neuroendocrine-Transition (TNT).
Citation Format: Daniel J. Salas-Escabillas, Megan T. Hoffman, Sydney M. Brender, Jacee S. Moore, Hui-Ju Wen, Simone Benitz, Erick T. Davis, Daniel Long, Allison Wombwell, Nina G. Steele, Brittany Allen-Petersen, Rosalie C. Sears, Ichiro Matsumoto, Kathleen E. DelGiorno, Howard C. Crawford. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of 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 C067.
Abstract C069: A conserved reepithelialization program driven by FOSL1 underlies malignancy in pancreatic ductal adenocarcinoma
Authors: David Charles , Zhuo Melian , Li Yong , Zhang Yifeng , Yang Chenlu , Deng Ziqing , Zhao Yupei , Wu Wennming , Peng Junya , Chen Mo 
Published: September 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 C072: Bmi1 expression is upregulated in response to injury/stress in the pancreas
Authors: Renollet Nur Muhammad , Thompson Joyce K , Wu Emily , Alkhalili Osama , Steele Nina , Bednar Filip 
Published: September 2024

Abstract
Pancreatic homeostasis is regulated in part through epigenetic mechanisms that restrict or enable access of pancreatic lineage transcription factors to their target genes. These epigenetic protein cascades are also required for regeneration of the pancreas after injury. B-cell Moloney murine leukemia virus integration site 1 (Bmi1), a central protein in the Polycomb repressor complex 1 (PRC1), has been shown to be required for the regeneration of the pancreas after injury and its absence prevents pancreatic neoplasia in mice. Previous work also suggests that Bmi1 marks a subset of acinar cells contributing to pancreatic renewal and tissue maintenance. It remains unclear how Bmi1 expression levels are regulated in response to pancreatic stress and injury. Here we assess the baseline expression of Bmi1 in pancreatic tissue with a genetic reporter mouse model as well as changes in Bmi1 mRNA levels at different time points after the induction of pancreatitis in wild-type mice via RNA in situ hybridization (RNAscope). We also compare the ability of the murine pancreas to regenerate after acute pancreatitis in the presence and absence of Bmi1. Our data indicates that rather than a specific subpopulation, most, if not all, acinar cells in the pancreas express Bmi1 during their life and specific loss of Bmi1 in the pancreas impairs regeneration after acute pancreatitis. We also show an increase in Bmi1 mRNA levels within the pancreas shortly after the induction of acute pancreatitis which reduces as the pancreas resumes its normal histology. Altogether, our data indicate that Bmi1 expression is dynamic, responsive to injury and necessary for pancreatic homeostasis and regeneration.
Citation Format: Nur Muhammad Renollet, Joyce K Thompson, Emily Wu, Osama Alkhalili, Nina Steele, Filip Bednar. Bmi1 expression is upregulated in response to injury/stress in the pancreas [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 C072.
Abstract C076: Transcriptomic analyses of normal human pancreatic acinar cells reveal the presence of cancer subtypes that correlate with acinar ductal metaplasia
Authors: Perkins Corey M , Jiang Jinmai , Greenberg Zachary , Talha Siddique Md Abu , Williams Linda C , Brant Jason O , Shirlekar Kalyanne , Han Bo , Ali Jamel , Fredenburg Kristianna M , Graim Kiley , Wilkie Diana J , He Mei , Schmittgen Thomas D 
Published: September 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 C077: Functional Dissection of the Highly Plastic Basal Cell State in Pancreatic Cancer
Authors: Singhal Anupriya , Styers Hannah C. , Rub Jonathan , Li Zhuxuan , Tarcan Zeynep , Hallin Jill , Basturk Olca , Yaeger Rona , Christensen James G. , Betel Doron , Yan Yan , de Stanchina Elisa , Tammela Tuomas 
Published: September 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 C078: Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes
Authors: MacPherson-Hawthorne Kevin , Link Jason M. , Worth Patrick , Sheppard Brett , Fields Andrew , Daniel Colin , Nishida Andrew , Pelz Carl , Waugh Trent , Agritelle Ethan , Muschler John , Adey Andrew , Sears Rosalie 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) disease progression involves complex cell state transitions in both malignant and non-malignant populations within the tumor microenvironment. To uncover PDAC cell states and epigenetic features associated with clinical outcome, we profiled 40 tumor samples (33 primary tumors and 7 metastases) from 39 patients with single cell ATAC-seq, along with 10 sample-matched single cell RNA-seq profiles. Through topic modeling of high dimensional chromatin data, we uncovered distinct cis-regulatory networks underlying the classical and basal-like molecular subtypes of PDAC, which showed differential activity in basal-classical hybrid cells. Furthermore, delineation of epigenetic alterations by basal, classical, and hybrid subtypes revealed a core set of chromatin regions opened in all PDAC subtypes relative to ductal and acinar cells. These universally open regions showed striking overlap with gastrointestinal enhancers, highlighting a common endoderm lineage infidelity process across pancreatic tumors. Within the stromal compartment, we identified novel regulators of myofibroblastic cancer-associated fibroblasts (myCAFs) and inflammatory CAFs (iCAFs) from enhancer networks active in each CAF subtype. Importantly, our data uncover a highly prognostic gene program active in only one of two distinct myCAF chromatin states found in our data, highlighting a putative tumor-promoting myCAF subpopulation. Our work provides a high-resolution description of epigenetic cell state heterogeneity in PDAC, revealing novel regulators and gene programs associated with PDAC subtypes and clinical outcome.
Citation Format: Kevin MacPherson-Hawthorne, Jason M. Link, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelle, John Muschler, Andrew Adey, Rosalie Sears. Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes [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 C078.
Abstract C079: Exploring acinar to ductal metaplasia in pancreatitis and precancerous contexts using FixNCut
Authors: Aney Katherine , Jeong Woo-Jeong , Koak Pal , Kim Isabel , Nissim Sahar 
Published: September 2024

Abstract
Acinar to ductal metaplasia (ADM) is the process by which acinar cells transition to a duct-like state acquiring ductal markers and morphology. This process can be driven by pancreas inflammation or injury, such as pancreatitis, where it is thought to be an adaptive response to help mitigate damage and facilitate repair. ADM is also observed following acinar-specific oncogenic KRAS mutations and known to precede PDAC precancerous lesions termed pancreatic intraepithelial neoplasias (PanINs). While ADM is well characterized histologically, cellular and molecular details of ADM and PanIN formation remain less well understood, in part due to high levels of digestive enzyme production in acinar cells that hamper characterization. Leveraging our recently described DSP-fixation method, FixNCut, to improve capture and transcriptome quality of acinar and ADM populations in the pancreas, we characterize ADM arising in three contexts: acute pancreatitis, recurrent acute pancreatitis, and acute pancreatitis with an oncogenic KRAS mutation known to drive the formation of PanINs. FixNCut and single-cell RNA-sequencing enabled us to elucidate the transcriptomic landscape of ADM and define changes to the microenvironment in unprecedented detail. Our findings indicate that the cellular and transcriptional landscape of recurrent acute pancreatitis closely mirrors that of acute pancreatitis for up to 6 weeks (or 6 bouts of 2-day acute pancreatitis), which was the longest timepoint tested. In contrast, acute pancreatitis in the presence of an acinar-specific oncogenic KRAS mutation results in a distinct transcriptional profile for both ADM and the surrounding microenvironment compared to pancreatitis alone. Additionally, we use FixNCut to preserve the epigenomes of acinar cells, enabling us to sort acinar cells and profile their histone modifications in various contexts of ADM. We benchmark and validate our results against existing mouse and human datasets of precancer and cancer. Through this work, we aim to enhance our understanding of ADM in various contexts, providing insights into acinar cell plasticity and early PDAC precursor formation that may inform strategies for early detection and interception.
Citation Format: Katherine Aney, Woo-Jeong Jeong, Pal Koak, Isabel Kim, Sahar Nissim. Exploring acinar to ductal metaplasia in pancreatitis and precancerous contexts using FixNCut [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 C079.
Abstract IA-02: The tumor-reactive CD8+ T-cell repertoire in pancreatic cancer as revealed by single-cell sequencing
Authors: Offringa Rienk 
Published: September 2024

Abstract
We recently reported on the analysis of the tumor-infiltrating T-cell repertoire in human pancreatic cancer by means of single cell RNA-sequencing (scRNA-seq), demonstrating the presence of expanded tumor-reactive CD8+ TCR clonotypes in these tumors (Sci Transl Med 2023 Nov 15;15(722):eadh9562). In view of the low numbers of somatic mutations in pancreatic cancer, we chose to perform an unbiased screening against autologous tumor cells rather than against predicted mutanome-encoded neoepitopes as performed in other recent studies. Systematical testing of tumor-reactive TCRs against predicted neoepitopes thus far did not result in hits, suggesting that linear, mutanome-encoded peptides may not represent the immunodominant T cell epitopes targeted by the natural T-cell response. In parallel, we conducted a similar analysis of the tumor-infiltrating T-cell repertoire in two distinct syngeneic mouse models for pancreatic cancer from which we isolated &gt; 100 tumor-reactive TCRs. While some of these TCRs were exclusively reactive against the tumor of origin, we found most to react against recurrent tumor antigens. By means of immunopeptidome analyses, we identified a number of T-cell epitopes that reflect this reactivity pattern: a ‘private’ mutanome-encoded neoepitope and several epitopes derived from over-expressed tumor-associated autoantigens. In a third, complementary study, we addressed the question whether T-cell receptors (TCRs) raised through immunization with tumor-specific neoepitopes, as identified by mutanome analysis and HLA-peptide binding algorithms in human pancreatic cancer, would duly mediate T-cell reactivity against the autologous tumors in which the epitope-encoding mutations were identified. We therefore immunized humanized (human TCR-locus, HLA-transgenic) mice with synthetic peptides representing 18 carefully selected candidate neoepitopes. For 4 of these epitopes, we successfully isolated fully human TCRs that specifically recognize naturally processed neoepitopes on tumor cells. Taken together, our studies demonstrate that pancreatic cancer can be targeted by T-cells directed against neoepitopes and tumor-associated autoantigens, but also raise important questions concerning the pros and cons of these options.
Citation Format: Rienk Offringa. The tumor-reactive CD8+ T-cell repertoire in pancreatic cancer as revealed by single-cell 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 IA-02.
Abstract IA-03: Functional heterogeneity of fibroblast populations in pancreatic cancer
Authors: Biffi Giulia 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is especially lethal among cancers because current treatments are few and ineffective. One key stromal factor thought to contribute to the dismal prognosis of PDAC is the presence of cancer-associated fibroblasts (CAFs). However, CAF-targeting therapeutic strategies have so far failed. Recently, providing an explanation for this apparent contrasting observations, phenotypically distinct PDAC CAF subtypes have been discovered. We previously described two main PDAC CAF populations that are defined by distinct targetable molecular mechanisms: TGF-beta-dependent myofibroblastic CAFs (myCAFs) and IL-1-dependent inflammatory CAFs (iCAFs) (J Exp Med 2017). We also demonstrated how the activation of one pathway (i.e., TGF-beta signaling) blocks the activation of another (i.e., IL-1 signaling), leading to this CAF heterogeneity (Cancer Discovery 2019). Despite our progress, the roles of distinct PDAC CAF subtypes remain to be largely elucidated. Indeed, the ability of myCAFs and iCAFs to at least partially interconvert and the lack of genetically engineered mouse models (GEMMs) for their in vivo manipulation have so far hindered careful investigation of their functions in PDAC progression. To overcome these challenges, we have engineered new mouse models and ‘CAF-locked’ fibroblast lines that enable to alter CAF composition in vitro and in vivo. Leveraging these new models, we are starting to understand the respective crosstalk of iCAFs and myCAFs with each other, with PDAC malignant cells, with immune cells and with other stromal cells. Improving PDAC survival for all patients will likely require a better understanding of the complex nature of the tumor microenvironment in these heterogeneous cancers. While further genetic manipulation of myCAF (e.g., EGFR-activated myCAFs – Cancer Cell 2024) and iCAF subsets will be required to achieve that, our studies are crucial to begin to decipher this complexity.
Citation Format: Giulia Biffi. Functional heterogeneity of fibroblast populations 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 IA-03.