bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C041: Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts
Authors: Woogeng Ivo N. , Han Lu , Saberi Samaneh , Bumbleburg Cameron , Beaudet Joseph , Sharma Sudarshana , Ostrowski Michael 
Published: January 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy with poor prognosis and treatment options. Cancer associated fibroblasts (CAFs) play a complex role in the PDAC tumor microenvironment (TME), contributing significantly to the progression of the tumor and the dense desmoplastic stroma. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss in both the tumor and in CAFs is associated with increased tumor aggressiveness and resistance to therapy. Our group previously demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which correlated with worsened outcomes. In addition, PTEN expression was lost in 80% of SMA+ CAFs in mouse PDAC models. Genetic or pharmacologic inhibition of the hedegehog pathway leads to ubiquitin-dependent destruction of PTEN by the proteosome. However, little is known of the signals produced by tumor cells that trigger PTEN degradation in CAFs. In order to address this problem, we developed an in vitro assay system based on wild type murine PDAC-CAFs that expresses a PTEN-GFP fusion protein. Initially, we focused on IL6 and IL6 family members Leukemia Inhibitory Factor (LIF) and Oncostatin-M (OSM) and Transforming Growth Factor beta 1 (TGFb1). The SMO inhibitor GDC-0449 was used as a positive control. PTEN stability was evaluated using the LSM 880 confocal microscope and GFP+ cells were quantified with QuPath-0.4.3 and analyzed with GraphPad Prism. Among the repertoire of secreted factors, we found that only OSM and TGFb1 could destabilize PTEN after 48H of treatment. When queried against the single cell RNA sequence dataset produced by our lab, we observed that CD45+ leukocytes were the likely source of OSM whereas TGFb1 was produced by tumor cells, fibroblasts, and immune cells. In conclusion, OSM and TGFb1 can downregulate PTEN in CAFs in vitro. Current efforts are aimed at testing whether inhibition of these pathways can restore PTEN expression in mouse PDAC models, and in identifying signaling pathways and E3-ligases that mediate PTEN destruction. These pathways and interactions could be further exploited for selective inhibition aimed at therapeutic benefits in curbing PDAC progression.
Citation Format: Ivo N. Woogeng, Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma, Michael Ostrowski. Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts [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 C041.
Abstract C063: Keratin 17 as a predictor of chemotherapy response in pancreatic ductal adenocarcinoma
Authors: Oblein Lyanne , Roa Lucia , Babu Sruthi , Horowitz Michael , Petricoin Emanuel , Matrisian Lynn M. , Blais Edik , Marchenko Natalia , Allard Felicia , Alkalin Ali , Jiang Wei , Larson Brent , Hendifar Andrew , Picozzi Vincent , Choi Minsig , Escobar-Hoyos Luisa , Shroyer Kenneth 
Published: January 2024

Abstract
Background: Two chemotherapies based on either gemcitabine- or 5-fluorouracil (5-FU) remain standard-of-care for pancreatic ductal adenocarcinomas (PDACs). Patients, however, differ in response and thus many clinical trials for experimental drugs have failed. Therefore, there is an urgent need to establish clinically deployable and rapid biomarkers to decide the best chemotherapeutic regimen for subgroups of patients and prevent toxic side effects. We previously reported that keratin 17 (K17) expression, detected at either the level of messenger RNA or protein by immunohistochemistry (IHC), is as accurate as molecular subtyping to identify subgroups of PDAC patients with shortest survival. In this work, we determined the predictive value of K17 testing for both chemotherapeutic approaches to treat PDAC. Methods: We profiled keratin 17 (K17) expression, a hallmark biomarker of the basal molecular subtype of PDAC, using immunohistochemistry in two cohorts of formalin-fixed paraffin-embedded PDACs (total n=305). These cases were collected through the Know Your Tumor® initiative and three high-volume treating institutions in the U.S. We performed multivariate predictive analyses and determined the threshold to define positive vs negative test. Results: Patients with advance stage disease, low K17, and treated with 5-FU- chemotherapy had three-times longer survival rates compared to counterparts treated with gemcitabine-based chemotherapy. These results contrast to those found in cases with high K17, where no differences were seen with either regimen. Based on RECIST, 72% of low K17 cases responded to treatment compared to 24% of high K17 cases. Predictive value of K17 was independent of mutation status and clinical variables. Conclusions: Our findings indicate that 5-FU-, rather than gemcitabine- based therapies are more likely to extend survival for patient's tumors expressing low rather than high K17. A K17 IHC test rapid test in PDACs has been patented (US11,092,603) and it is currently being tested in prospective phase II clinical trials (NCT04469556, NCT02047474 and NCT03991962). Results from these trials will test the presented findings.
Citation Format: Lyanne Oblein, Lucia Roa, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn M. Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Luisa Escobar-Hoyos, Kenneth Shroyer. Keratin 17 as a predictor of chemotherapy response 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 C063.
Abstract C103: Differential acquisition of extracellular lipid correlates with pancreatic cancer subtype and metastatic tropism
Authors: Rademaker Gilles , Hernandez Grace A. , Qiu Longhui , Wen Kwun W. , Jain Aakriti , Kim Grace A. , Zoncu Roberto , Perera Rushik M. 
Published: January 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 C107: Use of spatial transcriptomics to identify molecular features associated with African American heritage in pancreatic cancer
Authors: Wu Yuesong , Xie Aoqi , Loveless Ian , George Madison , Gartrelle Kendyll , Clark Julie , Salas-Escabillas Daniel , Shah Rupen , Kwon David , Francescone Ralph , Vendramini Costa Débora B. , Crawford Howard , Theisen Brian , Cui Yuehua , Huang Ling , Steele Nina G. 
Published: January 2024

Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths in the US, with a 5-year survival rate of 12%. Black or African American patients (BAA) have a 20% higher incidence of pancreatic cancer, and recent studies suggest that there are biological factors that may influence this disparity, in addition to complex socioeconomic factors. Pancreatic tumors are highly enriched with stroma and exhibit significant inter- and intra-patient morphological and molecular heterogeneity. To improve the care for all patients, we need to better understand the disease mechanisms by comprehensively mapping different spatial locations within individual patients’ tumors and determining whether there are common patterns of pathogenesis across diverse patient populations. In this study, we utilized the 10X Visium spatial transcriptomics platform on eight treatment-naïve primary pancreatic tumors. We tested multiple published bioinformatic packages, including SpatialDE, SPARK-X, Spatial PCA, and Cottrazm, and optimized a multi-sample integrated analysis pipeline that allows us to automatically segment tumor lesions, infer major cell types in regions of interest on tissues, detect spatially variant genes, and assess associations between tissue morphological phenotypes and transcriptomic features. Importantly, our study cohort includes four White patients and four BAA patients. Through the comparison of spatial transcriptomes between White and BAA patients, we identified several genes displaying differential expression in tumor lesions of distinct racial groups, including Trefoil Factor 1 (TFF1) and CYP3A5. These genes present potential candidates for further investigation to elucidate the biological mechanisms underlying racial disparities in pancreatic cancer.
Citation Format: Yuesong Wu, Aoqi Xie, Ian Loveless, Madison George, Kendyll Gartrelle, Julie Clark, Daniel Salas-Escabillas, Rupen Shah, David Kwon, Ralph Francescone, Débora B. Vendramini Costa, Howard Crawford, Brian Theisen, Yuehua Cui, Ling Huang, Nina G. Steele. Use of spatial transcriptomics to identify molecular features associated with African American heritage 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 C107.
Abstract IA13: Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer
Authors: Califano Andrea 
Published: January 2024

Abstract
Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of regulatory protein activity in single cells identified three PDA Developmental Lineages (PDLs), coexisting in virtually all tumors, whose transcriptional states are mechanistically driven by aberrant activation of Master Regulator (MR) proteins associated with gastrointestinal lineages (GLS state), morphogen and EMT pathways (MOS state), and acinar-to-ductal metaplasia (ALS state), respectively. Each PDL is further subdivided into sub-states characterized by low vs. high MAPK pathway activity. This taxonomy was remarkably conserved across multiple cohorts, cell lines, and PDX models, and harmonized with bulk profile analyses. Cross-state plasticity and MR essentiality was confirmed by barcode-based lineage tracing, epigenetic profiling, and CRISPR/Cas9 assays, respectively. Indeed, ectopic expression of PDL-specific MRs induced transdifferentiation in vitro and in vivo. Together these data provide a mechanistic foundation for PDA heterogeneity and a roadmap for targeting PDA cellular subtypes.
Citation Format: Andrea Califano. Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA13.
Abstract IA14: Forecasting pancreatic carcinogenesis through spatial multi-omics
Authors: Fertig Elana J. 
Published: January 2024

Abstract
Combining genomics with mathematical modeling provides a forecast system that can yield computational predictions to anticipate cancer progression and therapeutic response. High-throughput profiling technologies can indicate the molecular and cellular pathways of malignancies, but not the effect of targeting those pathways with therapy. Precision interception requires relating therapies to the cellular phenotypes underlying pancreatic carcinogenesis. This talk presents a hybrid computational and experimental strategy to uncover interactions between neoplastic cells and the microenvironment during pancreatic carcinogenesis. As pancreatic cancer develops, it forms a complex microenvironment of multiple interacting cells. The microenvironment of advanced pancreatic cancer includes a heterogeneous and dense population of cells, such as macrophages and fibroblasts, that are associated with immunosuppression. New single-cell and spatial molecular profiling technologies enable unprecedented characterization of the cellular and molecular composition of the microenvironment. These technologies provide the potential to identify candidate therapeutics to intercept immunosuppression in pancreatic cancer. State-of-the-art mathematical approaches in computational biology are essential to uncover mechanistic insights for high-throughput data for these precision interception strategies. We have recently applied new machine learning techniques to integrate imaging and spatial transcriptomics to enable comprehensive characterization of the pancreatic precancer microenvironment. Developing targets for interception requires determining which of these cellular and molecular pathways drive subsequent development of cancer. Relating the transcriptional programs in premalignant lesions to carcinogenesis requires mapping their temporal changes across disease stages. To integrate the spatial molecular data from premalignancies and single-cell RNA-seq reference atlases, we developed a transfer learning approach. This integrated analysis identified a switch between fibroblast-induced inflammatory signaling and cellular proliferation in pancreatic cancer cells. We confirmed these transitions also occur in pancreatic cancer patient derived organoids co cultured with fibroblasts using transfer learning from the reference scRNA-seq atlases of pancreatic tumors. This approach demonstrates the potential of computational analysis of multi-omics data in human tissue with organoid models for bidirectional bench to bedside research.
Citation Format: Elana J. Fertig. Forecasting pancreatic carcinogenesis through spatial multi-omics [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 IA14.
Abstract IA15: What the surgeon has learned from pancreas cancer genomics, and vice versa
Authors: Gallinger Steven 
Published: January 2024

Abstract
Recent advances in molecular profiling and fundamental science discoveries are impacting care of PDAC patients, including surgical decision making. Our multidisciplinary group at the Ontario Institute for Cancer Research and the Princess Margaret in Toronto has focused on elucidating both germline and somatic genomic changes in PDAC, with aims to understand genetic predisposition to the disease, foster early detection and conduct trials for improved selection of standard and novel therapies. Using laser capture microdissection overseen by expert pathologists, seamless tumor banking and aggressive biopsy of chemo-naïve and progressive metastases, we have generated high epithelial tumor cell content whole genomes and transcriptomes (WGTS) on over 600 PDAC patients with all stages of the disease. Germline sequencing of all PDAC patients should be considered standard of care to detect patients with uniquely actionable genomic changes due to less common mutational pathways. The genetic basis of familial pancreas cancer remains elusive and we continue to collaborate with the PACGENE Network spearheaded by colleagues at Mayo, Hopkins and McGill to discover novel genes in high risk cases. Our genomic work and others explains the clinical conundrum of late presentation of PDAC due to rapid punctuated evolution which challenges the ‘holy grail’ of early detection. Thus, screening high risk groups is still within the realm of investigational studies such as the PRECEDE consortium, of which we are an active member. Focused clinical trials (eg COMPASS and PASS-01) using WGTS has revealed both large scale changes in genomes (eg. HRD, tandem duplicators, etc) and transcriptomes (the Moffit ‘continuum’) and discreet mutations (eg BRAF mutations in Kras wild type tumors) that are important to identify as early as possible in the patient’s clinical course. Subspecialty PDAC surgeons need to keep abreast of recent developments of both prognostic and predictive transcriptomic biomarkers that will soon be important in selecting appropriate patients for appropriate neoadjuvant therapies. A few clinical vignettes will be shown to provide evidence for the importance of WGTS and other profiling approaches for almost all PDAC patients.
Citation Format: Steven Gallinger. What the surgeon has learned from pancreas cancer genomics, and vice versa [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 IA15.
Abstract IA20: Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
Authors: Han Jincheng , Xu Jiaqian , Liu Yonghong , Liang Shaoheng , LaBella Kyle A. , Chakravarti Deepavali , Spring Denise J. , Xia Yan , DePinho Ronald A. 
Published: January 2024

Abstract
Oncogenic KRAS (KRAS*) is a signature mutation in pancreatic ductal adenocarcinoma (PDAC). While genetic extinction or pharmacological inhibition of KRAS* elicits anti-tumor responses in preclinical models and patients, we and others have identified cancer cell intrinsic (YAP, RTKs) and paracrine immune-mediated (TGFb) mechanisms enabling KRAS* bypass and tumor recurrence. Here, we explored the potential role of cancer associated fibroblasts (CAFs) as contributors to mechanisms driving KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent tumor regrowth is supported. We showed that genetic extinction or pharmacological inhibition of KRAS* results in upregulation of ERBB2 and ERBB3 expression in human and murine cancer cell models. We demonstrated that CAF-derived NRG1 supports KRAS*-dependent tumor growth. These insights prompted genetic depletion or pharmacological inhibitions studies targeting ERBB2/3 or NRG1, which showed abolition of KRAS* bypass and synergy with KRASG12D inhibitor in mouse and human PDAC models. Thus, CAFs via the NRG-ERBB2/3 paracrine axis provide yet another mechanism enabling KRAS* inhibitor therapy resistance, providing a highly actionable combination therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
Citation Format: Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A. LaBella, Deepavali Chakravarti, Denise J. Spring, Yan Xia, Ronald A. DePinho. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas 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 IA20.
Abstract PR13: Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer
Authors: Rajbhandari Nirakar , Hamilton Michael , Reya Tannishtha 
Published: January 2024

Abstract
The detailed understanding of the molecular basis of tumor initiation and progression is essential for the effective management and treatment of any cancer, including pancreatic cancer. To determine if the stem and progenitor cells can serve as cells of origin for pancreatic cancer, we have created a new mouse strain in which tamoxifen inducible Cre (CreERT2) is knocked into the endogenous locus encoding the stem cell regulator Musashi2 (Msi2). When crossed to a Cre-regulatable Myc transgenic (CAG-LSL-MycT58A) strain, Msi2-CreERT2 mice develop multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), and acinar cell carcinoma (ACC) following Myc activation in Msi2+ cells in the adult stage. A combination of single-cell genomics with computational analysis of developmental states and lineage trajectories of tumors in our model suggests that oncogenic Myc preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage potential. These pre-cancer cells subsequently take distinct fates within the same mice by activation of distinct transcriptional programs and large-scale genomic changes. Additionally, combining transcriptomic and functional genomic approaches, we have identified hyaluronan-mediated motility receptor (HMMR) as a potential novel dependency in mouse and human ASCP cells, providing a framework to develop interception strategies for this lethal disease. In summary, our study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer.
Citation Format: Nirakar Rajbhandari, Michael Hamilton, Tannishtha Reya. Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR13.