tbuckley/cabot-search huggingface dataset:
Abstract PR-19: Cell polarity proteins as novel regulators of macropinocytosis
Authors: Guillem Lambies Barjau, Szu-Wei Lee, Karen Duong-Polk Duong-Polk, David Dawson, Cheska Marie Galapate, Swetha Maganti, Cosimo Commisso
Journal: Cancer Research (2024)

Abstract Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCz and PKCi, as novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the microtubule-associated Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion in glutamine stress is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for the cell polarity protein network in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress. Citation Format: Guillem Lambies Barjau, Szu-Wei Lee, Karen Duong-Polk Duong-Polk, David Dawson, Cheska Marie Galapate, Swetha Maganti, Cosimo Commisso. Cell polarity proteins as novel regulators of macropinocytosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-19.
Abstract B032: Evaluating T cell-inflammation in pancreatic neuroendocrine tumors
Authors: Joan Miguel Romero, James Vafiadis, Tess Aalto, Ruomeng Fang, Yifan Wang, George Zogopoulos
Journal: Cancer Research (2024)

Abstract Background: Pancreatic neuroendocrine tumors (pNETs) are rare tumors arising from neuroendocrine cells in the pancreas. Their clinical behaviour and prognosis are variable and durable responses are often difficult to achieve with conventional therapies. Immunotherapy approaches may be efficacious in a subgroup of pNETs. In a recent study that did not include pNETs, we showed that a four-chemokine signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) predicts T cell-inflammation and response to immune checkpoint inhibitors across cancers. We have hypothesized that the c-Score will also identify pNET subgroups with T cell-inflammation. Methods: The c-Score and hallmarks of the cancer-immunity cycle are being evaluated in pNETs as a cohort study (n=100 cases) of the Marathon of Hope Cancer Centres Network whole genome and transcriptome tumor sequencing (WGTS) project. The cohort study will compare pNET profiles with those of other pancreatic and peri-ampullary tumors. Results: As of June 1, 2024, primary tumor data from 23 cases were available for analysis, including 16 pNETs, 2 pancreatic ductal adenocarcinomas (PDAC), 2 pancreatic adenosquamous carcinoma (PASC), 2 distal cholangiocarcinomas (dCCA), and 1 ampullary carcinoma (AC). Dimension reduction by principle component analysis (PCA) revealed clustering based on histological subtype. Interestingly, PCA using immune genes also demonstrate subgrouping that overlapped with the histological subtypes, suggesting that immunity of pancreatic/peri-ampullary neoplasms may be directed by histological types rather than the pancreas gland itself. These cancers showed a broad distribution of c-Score expression, with pNETs having the lowest c-Score. Tumors with high expression of the c-Score, including 2 pNETs, had increased expression of cancer-immunity cycle gene sets. DUX4, FAM186A, and IGFN1 were amongst the most common genes mutated in all tumors. Conclusions: Early data suggest that pNETs generally harbor low c-Score values and hallmarks of cancer-immunity, with the existence of a subgroup of pNETs displaying T cell-inflammation. Citation Format: Joan Miguel Romero, James Vafiadis, Tess Aalto, Ruomeng Fang, Yifan Wang, George Zogopoulos. Evaluating T cell-inflammation in pancreatic neuroendocrine tumors [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 B032.
Abstract A034: KRAS Mutation-Specific effects on the Tumor Immune Microenvironment Drive Tumor Progression
Authors: None Andrew wenger, Tal Baron, Erika Hissong, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Rohit Chandwani, Lukas Dow, Despina Siolas
Journal: Cancer Research (2024)

Abstract The immune microenvironment plays a critical role in cancer development, progression and resistance to therapy. KRAS mutations are near-ubiquitous in pancreatic ductal adenocarcinoma (PDAC) and several studies have demonstrated that KRASG12D can create an immunosuppressive tumor microenvironment. However, the immune effects of other oncogenic KRAS variants, such as KRASG12R (representing 20% of PDAC cases) are unknown. Given that specific KRAS mutants display distinct molecular phenotypes, we examined the immune cell composition of KRASG12R pancreatic tumors. Orthotopically implanted mouse tumors derived from KrasG12R/+;Trp53KO pancreatic organoids have a distinct immune profile in comparison to KrasG12D/+;Trp53KO tumors, characterized by an influx of intratumoral CD4+ T cells and mature dendritic cells. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link KRASG12R to a unique immune landscape that is distinct from KRASG12D tumors. Citation Format: Andrew wenger, Tal Baron, Erika Hissong, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Rohit Chandwani, Lukas Dow, Despina Siolas. KRAS Mutation-Specific effects on the Tumor Immune Microenvironment Drive Tumor Progression [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 A034.
Abstract C063: Inhibition of PRMT5 reduces aggressiveness in basal-like pancreatic ductal adenocarcinoma
Authors: Christina Wang, Zamira Guerra Soares, Dakarai Esgdaille, Stephano Spano Mello
Journal: Cancer Research (2024)

Abstract The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology is crucial for unraveling the intricacies of PDAC plasticity and developing effective treatment strategies for this aggressive tumor. Recent studies from our laboratory have shown that protein arginine methyl transferase 5 (PRMT5) significantly contributes to PDAC plasticity and progression towards the basal-like subtype. Specifically, our data show that patients with high levels of PRMT5 expression have a worse outcome, thus arguing that PRMT5 plays a role in PDAC aggressiveness and outcome. Moreover, our experiments indicate that inhibiting PRMT5, either genetically or chemically, in basal-like PDAC cells induces the expression of epithelial markers like GATA6 and E-CADHERIN, suggesting that PRMT5 promotes mesenchymal features in PDAC. Using wound healing and transwell assays, we have demonstrated that pharmacological inhibition of PRMT5 significantly suppresses cell migration and invasion. Additionally, colony formation and cell proliferation are markedly reduced upon PRMT5 inhibition in basal-like PDAC. Collectively, these findings suggest that inhibiting PRMT5 can effectively constrain the aggressive cellular features characteristic of basal-like PDAC, such as cell proliferation, clonogenicity, and migration. Recent research indicates that PRMT5 preferentially methylates splicing factors in various cell types, implying that RNA splicing regulation is crucial to PRMT5’s role in enhancing tumor plasticity and aggressiveness. We are currently investigating whether PRMT5-mediated RNA splicing alterations contribute to the maintenance of the basal-like PDAC phenotype. These studies provide key evidence that PRMT5 is essential for maintaining the aggressive characteristics of basal-like PDAC, highlighting its potential as a therapeutic target for this challenging cancer subtype. Citation Format: Christina Wang, Zamira Guerra Soares, Dakarai Esgdaille, Stephano Spano Mello. Inhibition of PRMT5 reduces aggressiveness in basal-like 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 C063.
Abstract B007: Optimization of an Orthotopic Mouse Model of Pancreatic Cancer to Simulate Liver Metastasis and Cancer Cachexia
Authors: David J Wang, Victoria Spadafora, Benjamin R Pryce, Alexander Oles, Erin E Talbert, Micheal C Ostrowski, Denis C Guttridge
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis due to two key features. The first is metastasis at presentation, occurring in approximately 80% of PDAC patients, with 90% of these metastases occurring in the liver. The second is cachexia, which compromises treatment tolerance and reduces the quality of life for patients. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. In this study, we optimized an orthotopic mouse model of PDAC by altering implantation sites, subcloning parental murine PDAC cells, adjusting the number of transplanted cells, and varying the age of recipient mice to study liver metastasis and cancer cachexia. These modifications significantly increased the latency of tumor development and the time course of the disease, concurrently increasing the rate of liver metastasis to approximately 70%. Furthermore, reliable cachexia endpoints were also achieved in both PDAC mice with and without metastases, mirroring the condition in patients. We also found that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. Together, this model is likely to be advantageous in both advancing our understanding of the mechanisms of PDAC cachexia and in evaluating novel therapeutics. Citation Format: David J Wang, Victoria Spadafora, Benjamin R Pryce, Alexander Oles, Erin E Talbert, Micheal C Ostrowski, Denis C Guttridge. Optimization of an Orthotopic Mouse Model of Pancreatic Cancer to Simulate Liver Metastasis and Cancer Cachexia [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 B007.
Abstract A075: Establishing the interaction mechanism of oncoprotein, Mucin1, and extracellular vesicle marker protein, Alix, in pancreatic cancer
Authors: Kristine V Hoagstrom, Ying Huang, Gloria E Borgstahl, Michael A Hollingsworth
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with devastating mortality rates largely due to a poor understanding of its progression mechanism. Small extracellular vesicles (sEVs) are used by cancer cells to aid in their progression, and tumor-derived EVs (TEVs) show a distinct protein cargo composition potentially contributing to this rapid progression and metastasis of PDAC. To investigate this phenomenon, we isolated sEVs from conditioned media of pancreatic cancer cell lines using ultracentrifugation and characterized them by transmission electron microscopy (TEM), nanoparticle tracking analysis, and immunoblotting. These sEVs were then used in several studies to investigate critical TEV cargo sorting machinery. For instance, PDAC-derived sEVs have selective enrichment of the oncogenic transmembrane protein Mucin1 (MUC1). Preliminary MUC1KO studies from our lab revealed that MUC1 potentially regulates sEV formation, where we saw a clear impact on sEV cargo in the absence of MUC1. Additional studies found that the cytoplasmic adaptor protein ALG-2-Interacting Protein X (Alix), a protein known to play a critical role during TEV formation, regulates MUC1’s presence in sEVs. From this discovery, we then identified a novel MUC1-Alix interaction, which was confirmed using several techniques, including co-immunoprecipitation (CoIP). To define the Alix-interacting domain of MUC1, we utilized in silico modeling and localized surface plasmon resonance (LSPR) of MUC1.CT and Alix to quantify the interaction. This revealed the cytoplasmic tail of MUC1 (MUC1.CT) as the Alix-interacting domain. Moving forward, our central hypothesis for this study is that this MUC1.CT-Alix interaction utilizes a conserved binding motif that targets Alix to the endosomal membrane and contributes to the formation of MUC1+ sEVs. While a distinct sEV biogenesis pathway employed by cancer cells has not yet been defined, our studies will provide insight into the potential sEV sorting mechanism of MUC1 and other cancer biomarkers and advance the understanding of PDAC progression. Citation Format: Kristine V Hoagstrom, Ying Huang, Gloria E Borgstahl, Michael A Hollingsworth. Establishing the interaction mechanism of oncoprotein, Mucin1, and extracellular vesicle marker protein, Alix, 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 A075.
Abstract PR-06: Dietary fats dictate pancreatic cancer fate via phospholipid saturation
Authors: Christian F Ruiz, Xiangyu Ge, Rylee McDonnell, Daniel McQuaid, Jennifer Kaplan, Guangtao Li, Michael C Rudolph, Fred F Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew Rodeheffer, Mandar D Muzumdar
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the US and is anticipated to become the second within the next decade. Epidemiologic studies support a strong link between high fat diet (HFD) consumption and increased PDAC risk, however, the translational relevance of diet research has been limited by inconsistencies in fat source and consumption across human populations and mouse studies. Therefore, whether and how specific dietary fatty acids drive cancer development is poorly understood. To address this gap in knowledge, we performed a diet screen, comprised of 12 isocaloric HFDs differing solely in fat source and representing the diversity of modern human fat consumption, in an oncogenic Kras-driven mouse model (KC: Kras LSL-G12D /+;Pdx1-Cre) that closely mimics the genetic and histologic features of human PDAC progression. Unexpectedly, we discovered that diets rich in oleic acid – a monounsaturated fatty acid (MUFA) typically associated with good health – enhanced pancreatic tumorigenesis. Furthermore, we observed a strong positive correlation between increased tumor burden and diets exhibiting a high ratio of MUFAs to polyunsaturated fatty acids (PUFAs), concordant with high MUFA to PUFA levels in the plasma and in pancreatic phospholipids. Membrane phospholipid incorporation of MUFAs (relative to PUFAs) suppresses lipid peroxidation and cell death via ferroptosis. Consistent with this, pancreata from mice fed a MUFA-rich diet showed decreased expression of genes involved in lipid peroxidation and reduced histologic evidence of lipid peroxidation end products compared to a PUFA-rich diets. Furthermore, primary acinar cells from mice fed high MUFA diets were resistant to cell death upon treatment with ferroptosis inhibitors. Conversely, diets rich in PUFAs increased PUFA incorporation into pancreatic phospholipids, activated transcriptional programs of lipid peroxidation, and intercepted Kras-driven tumor progression in vivo. Collectively, these data support a role for dietary fatty acids in molding the pancreatic phospholipid landscape, altering lipid peroxidation and ferroptosis sensitivity to dictate tumor fate. Citation Format: Christian F Ruiz, Xiangyu Ge, Rylee McDonnell, Daniel McQuaid, Jennifer Kaplan, Guangtao Li, Michael C Rudolph, Fred F Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew Rodeheffer, Mandar D Muzumdar. Dietary fats dictate pancreatic cancer fate via phospholipid saturation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-06.
Abstract A074: Integrated clinical and single-cell profiling analysis reveals cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma
Authors: Morteza Chalabi Hajkarim, Michael May, Amit Dipak Amin, Jacob Jamison, Somnath Tagore, Lindsay Caprio, Zachary Walsh, Parin Shah, Sinan Abuzaid, Alissa Michel, Sun Dajiang, Winston Wong, Neha Shaikh, Priyanka Ramaradj, Basil Bakir, Michael D Kluger, John Chabot, Hanina Hibshoosh, Anil K Rustgi, Alexander Raufi, Gulam A Manji, Benjamin Izar
Journal: Cancer Research (2024)

Abstract Some patients with localized pancreatic ductal adenocarcinoma (PDAC) undergo resection with curative intent, but most experience disease recurrence and succumb to their disease. Through examination of 743 PDAC patients in a single center we found that the site of first recurrence is a major predictor for survival. Patients with liver-metastatic recurrence (LIV-MR) had significantly shorter disease free and overall survival compared to those with recurrence to the lung (LUN-MR). We performed single-nucleus RNA-seq (snRNA-seq) and whole-genome sequencing (WGS) of primary PDAC with either LIV-MR or LUN-MR and found that malignant cells adopt transcriptional programs that mimicked that of their ultimate metastatic target organ. We validated this observation in independent data sets of human adult and fetal liver and lung tissues, and two additional patient cohorts who underwent molecular profiling of their actual PDAC liver and lung metastatic lesions. We reconstructed two different trajectories of malignant transformation in PDAC and found that the LIV-MR and LUN-MR are associated with these, suggesting that subsequent metastatic organotropism may be imprinted early in tumorigenesis. Furthermore, primary PDAC tumors recurring with LIV-MR compared to LUN-MR were depleted of infiltrating T cells and enriched with M2-like macrophages, highlighting potential contributions to subsequent outcomes. Taken together, this work provides evidence for pre-existing cellular adaptations that may determine metastatic organotropism in the context of cancer recurrence. These insights may be useful for prognostication and development of therapeutic strategies at the time of diagnosis of resectable PDAC. Citation Format: Morteza Chalabi Hajkarim, Michael May, Amit Dipak Amin, Jacob Jamison, Somnath Tagore, Lindsay Caprio, Zachary Walsh, Parin Shah, Sinan Abuzaid, Alissa Michel, Sun Dajiang, Winston Wong, Neha Shaikh, Priyanka Ramaradj, Basil Bakir, Michael D Kluger, John Chabot, Hanina Hibshoosh, Anil K Rustgi, Alexander Raufi, Gulam A Manji, Benjamin Izar. Integrated clinical and single-cell profiling analysis reveals cellular states associated with metastatic organotropism and survival in patients with 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 A074.
Abstract B023: Unravelling fibroinflammatory and immune signatures for pancreatic cancer early detection
Authors: Kyra Fraser, Maria Rosado, Stephen P Pereira, Pilar Acedo
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is associated with late-stage diagnosis and poor patient prognosis. The disease is characterised by chronic dysregulated immunity and inflammation. Moreover, chronic pancreatitis is linked with an increased risk of pancreatic cancer. Tissue remodelling during disease progression involves a complex network of cells and a crosstalk between cancer cells, stromal components and immune cells, but it remains poorly explored. Thus, to improve the outcome of patients, there is a need for better understanding of biological changes associated with the initiation and progression of pancreatic cancer at the molecular and spatial levels. Using samples obtained from our Accelerated Diagnosis of neuroEndocrine and Pancreatic TumourS (ADEPTS) biobank, we have evaluated blood samples for the discovery of non- invasive biomarkers to discriminate patients with pancreatic cancer from symptomatic patients without cancer. In this pilot study, the transcriptome of peripheral blood mononuclear cells (PBMCs), isolated using a ficoll gradient was explored to identify PDAC-associated mRNA signatures. Moreover, the Olink® Explore Inflammation and Oncology panels were performed in a cohort of 40 patients with early stage (I-II) PDAC, 40 chronic pancreatitis samples and 40 control patients with benign symptomatic upper GI diseases. To validate and enrich these results, a panel of inflammatory and immune markers including immunoglobulins, cytokines and chemokines was also run using multiplex techniques. Symptoms observed in our cohort were also analysed together with clinical (e.g diabetic status, biochemistry profile) and demographic data (age, sex, ethnicity, post code etc). We have identified mRNA transcriptome signatures and differentially expressed proteins associated with inflammatory and immunological processes in PDAC compared to benign symptomatic samples. Our results offer potential diagnostic utility for early-stage disease. Additionally, our unique cohort of patient samples comprising of those with confirmed PDAC and those presenting to clinic with benign disease and similar non-specific symptoms, allows for the development of non-invasive diagnostic tests with better translational applicability. Future work will involve the validation of these findings in a larger patient cohort and the use of NanoString GeoMx® Digital Spatial Profiler to perform whole transcriptome and proteome profiling in human chronic pancreatic and pancreatic cancer tissue samples. Citation Format: Kyra Fraser, Maria Rosado, Stephen P Pereira, Pilar Acedo. Unravelling fibroinflammatory and immune signatures for pancreatic cancer early detection [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 B023.