tbuckley/cabot-search huggingface dataset:
Abstract C066: Metaplastic tuft cells transdifferentiate into metaplastic neuroendocrine cells as pancreatic cancer progresses into late stage carcinoma
Authors: Daniel J. Salas-Escabillas, Jacee Moore, Dan Long, Megan Hoffman, Don Rempinski, Nina Steele, Howard Crawford
Journal: Cancer Research (2024)

Abstract Progression of pancreatic disease is in part driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that have the potential to drive tumor progression through communication with the microenvironment and modulate PDA progression. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have different roles depending on the organ in which they reside. Tuft cells are found in several different organs during normal development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model to of PDA due to a lack of mouse model as well as the complexity of culturing them ex vivo. We have generated a unique dual recombinase mouse model to drive lineage tracing of MTCs during PDA, and our data to suggests that MTCs are not disappearing as PDA progresses but can transdifferentiate into metaplastic neuroendocrine cells. Citation Format: Daniel J. Salas-Escabillas, Jacee Moore, Dan Long, Megan Hoffman, Don Rempinski, Nina Steele, Howard Crawford. Metaplastic tuft cells transdifferentiate into metaplastic neuroendocrine cells as pancreatic cancer progresses into late stage carcinoma [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 C066.
Abstract C040: Investigating oncogene-inflammation cooperativity in pancreatic cancer
Authors: Katharina Woess, Sandra Blázquez Araguás, Andrea Diéguez, Lidia Mateo, Direna Alonso Curbelo
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is generally diagnosed at advanced late stages when current treatments are usually ineffective. It is initiated from a poorly understood interplay between genetic mutations (mutant KRAS) and inflammatory insults that cooperatively remodel the pancreatic epithelium and its tissue environment. Through integrating innovative autochthonous mouse models, single-cell technologies, and genomics methods, we recently identified early, tumor-specific chromatin changes induced by cooperative effects between mutant KRAS and inflammation, and which establish functionally-relevant cell-cell communication networks that direct pancreatic tumorigenesis (Alonso-Curbelo et al. Nature 2021; Burdziak*, Alonso-Curbelo* et al. Science 2023). These findings provide a molecular and cellular framework to understand inflammation-driven tumorigenesis, and raise the possibility of harnessing epigenetically-dysregulated cell-cell communication traits of KRAS-mutant cells to detect or block PDAC development. Towards this end, we are currently combining single-cell multiomics, multiplexed tissue analyses, and functional approaches in pre-clinical models to identify how tissue signals shape the state and fate of early KRAS-mutant cells, define paracrine effects of these changes in reprogramming the immune microenvironment, and establish the functional significance of these interactions in disease progression. With the advent of inhibitors targeting mutant KRAS, we expect that the proposed dissection of the cell-cell crosstalk networks cooperating with mutant KRAS in driving tumor development will uncover tissue-level mechanisms that may be harnessed for the interception and rationale treatment of PDAC. Citation Format: Katharina Woess, Sandra Blázquez Araguás, Andrea Diéguez, Lidia Mateo, Direna Alonso Curbelo. Investigating oncogene-inflammation cooperativity 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 C040.
Abstract B006: Exosomal protein Eps8 as a new biomarker for pancreatic cancer
Authors: Kazunao Hayashi, Atsunori Tsuchiya, Shuji Terai
Journal: Cancer Research (2024)

Abstract Exosomes are extracellular vesicles containing nucleic acids, proteins, and lipids of approximately 100 nm, which are released from cancer cells to create a microenvironment favorable for their survival. Epidermal growth factor receptor pathway substrate 8 (Eps8), an exosomal protein, is reportedly associated with metastasis. We investigated the relationship between Eps8 in the serum exosomes of patients with pancreatic cancer and clinicopathological factors and examined the usefulness of exosomal Eps8 as a biomarker for pancreatic cancer. Methods: Serum exosomes of 93 patients with pancreatic disease (64 cases of pancreatic cancer, 12 cases of chronic pancreatitis, and 17 cases of IPMN) were extracted via ultracentrifugation, and Eps8 in exosomes were evaluated by western blotting. We analyzed 1) the clinicopathological factors of patients with pancreatic cancer, 2) the Eps8 positive rate in each disease, 3) the sensitivity, specificity, and positive predictive value of Eps8 for the diagnosis of pancreatic cancer, 4) the relationship between Eps8 and clinicopathological factors, and 5) compared and discussed between exosomal Eps8 and serum CA19-9. Results: The median patient age was 72 years (47–85), with 35 male and 29 female patients included in the study. The median body mass index was 20.8 kg/m2 (12–26.7 kg/m2). 1) Site Ph33/Pbt31, cStageIV/III/II/I: 28/11/14/11; 2) pancreatic cancer 59.4%, chronic pancreatitis 33%, IPMN 12%; 3) sensitivity 59.4. 4) In patients with pancreatic cancer, Eps8-positive patients had significantly higher ALT (p = 0.03), significantly less cancer (p = 0.04), lower IPMN complication rates, and more chronic pancreatitis and autoimmune diseases than the exosomal Eps8-negative patients. Stage I 64% (7/11), Stage II 36% (5/14), Stage III 64% (7/11) Stage IV 68% (19/28) 5) Exosomal Eps8 positivity (64%) was higher than serum CA19-9 positivity (45%) in Stage I. We also found some patients were negative for serum CA19-9 but positive for exosomal Eps8. Conclusion: Exosomal Eps8 has a higher positive rate in Stage I than serum CA19-9. Diagnosis with exosomal Eps8 may improve diagnostic performance for pancreatic cancer. Citation Format: Kazunao Hayashi, Atsunori Tsuchiya, Shuji Terai. Exosomal protein Eps8 as a new biomarker for 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 B006.
Abstract B007: Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker
Authors: Kazufumi Honda, Ayumi H. Kashiro, Michimoto Kobayashi, Keiko Takeuchi, Yuya Shizume, Takanori Oh, Chigusa Morizane, Susumu Hijioka, Satoshi Nara
Journal: Cancer Research (2024)

Abstract To reduce the mortality rate of pancreatic cancer, there is an urgent need to develop a biomarker that can efficiently screen for pancreatic cancer in blood tests. We had identified the unique processing of C-terminal amino acids of apolipoprotein A2 homodimers, we named it apolipoprotein A2-isoforms (apoA2-i). ApoA2-i consists of three isoforms with different C-terminal amino acids. Especially, we had reported that apoA2-ATQ/AT, known as the intermediate isoform, was significantly reduced in the bloodstream of pancreatic adenocarcinoma (PDAC) patients compared to healthy controls. However, previous reports were investigated using a research use only (RUO) reagent, which could not be used in clinical settings. We generated a novel ELISA for measuring apoA2-i under the Japanese medical device Quality Management System requirements, and measured the concentration of apoA2-i in 2,732 of plasma samples. The clinical equivariance and significance of apoA2i were evaluated by pre-specified endpoints. The point estimate of the area under the curve to distinguish between PDAC and healthy controls was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832–0.925] than for CA19-9 (0.849, 95%CI: 0.793–0.905) and achieved the primary endpoint. The cut-off apoA2-ATQ/AT of 59.5 μg/mL was defined based on 95% specificity in 2,000 healthy samples. The sensitivity of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) of PDAC was higher than that of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cut-off, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. ApoA2-ATQ/AT has equivalent or better clinical performance to CA19-9 as a blood biomarker. Citation Format: Kazufumi Honda, Ayumi H. Kashiro, Michimoto Kobayashi, Keiko Takeuchi, Yuya Shizume, Takanori Oh, Chigusa Morizane, Susumu Hijioka, Satoshi Nara. Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker [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 B007.
Abstract C068: Construction of preclinical study model for optimal anticancer drug selection using PDX model in pancreatic cancer
Authors: Ryota Tanaka, Kenjiro Kimura, Naoki Tani, Shimpei Eguchi, Ken Kageyama, Shuhei Kushiyama, Shigeaki Kurihara, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, Go Ohira, Akira Yamamoto, Takeaki Ishizawa
Journal: Cancer Research (2024)

Abstract Background: Translational research using the patient-derived xenograft (PDX) model is progressing rapidly and is also becoming widespread in pancreatic cancer research. Since PDX models retain the characteristics and the heterogeneity of the primary tumor, PDX models can be reflected in the effectiveness of the anticancer drug in human. The purpose of this study was to establish the PDX library of pancreatic cancer for preclinical study. Methods: The tissues of the pancreatic cancer were obtained from patients who underwent surgery at our hospital. Two PDX models were established using immunodeficient rats. One case was effective in gemcitabine plus nab-paclitaxel (GnP) therapy, and the other was ineffective in GnP therapy in preoperative treatment. 5-FU, CPT-11, L-OHP, GEM, and CDDP were administered to these PDX models once a week for 3 weeks. The primary endpoint was tumor shrinkage. Results: GEM was effective in PDX model in a case in which GnP therapy was effective in the clinical setting, in contrast, GEM was ineffective in PDX model in a case in which GnP was ineffective in the clinical setting. This result was correlated with actual clinical practice. Conclusions: In this study, single anticancer drug tests were performed on PDX models using immunodeficient rats. The efficacy of anticancer drugs was correlated with the clinical setting, indicating that our PDX models might be useful as a preclinical study model. We are currently conducting multi anticancer drug studies. Citation Format: Ryota Tanaka, Kenjiro Kimura, Naoki Tani, Shimpei Eguchi, Ken Kageyama, Shuhei Kushiyama, Shigeaki Kurihara, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, Go Ohira, Akira Yamamoto, Takeaki Ishizawa. Construction of preclinical study model for optimal anticancer drug selection using PDX model 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 C068.
Abstract B056: Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs
Authors: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson
Journal: Cancer Research (2024)

Abstract An innovative approach in pancreatic cancer (PC) research is to utilize large animal models which (i) would be useful for development of technologies that require a human-sized platform and (ii) would produce data that could have greater clinical relevance and accuracy compared to data produced by murine models. To this end, our group has been developing porcine PC models and has reliably induced PC in the KRAS G12D/p53 R167H Oncopig model. The objective of the present study was to generate a slower-growing, early-stage PC model with intraductal injection of adenoviral vector with a Keratin 8 promoter driving the expression of the Cre-Recombinase protein (Ad5mK8-nlsCre) in oncopigs which, we hypothesized, would produce pancreatic neoplasia restricted to the epithelium. Results We first confirmed with scRNA-seq and immunohistochemistry that Keratin-8 expression in the porcine pancreas was restricted to ductal and acinar cells. Using an ex vivo infection assay with the Ad5mK8-nlsCre vector in wild-type porcine pancreas, we then demonstrated that expression of Cre-recombinase was confined to epithelial cells. We then performed a dose-response study of ductal injection (laparotomy) of Ad5mK8-nlsCre (10(7)-10(10) pfu) in Oncopigs. At the planned 2-month endpoint, all Ad5mK8-nlsCre concentrations produced microscopic evidence of ductal hyperplasia, metaplasia, and nuclear atypia, with KRAS-G12D expression by immunohistochemistry. At the higher Ad5mK8-nlsCre concentration, there was increased ductal mucin production. Using an epithelial-specific AdCre vector, we produced microscopic epithelial neoplasia within the pancreas of the Oncopig. Conclusion While further follow-up and characterization is needed, this induction technique may yield a porcine model of early-stage PC, which could be useful to (i) study early tumor biology and progression and (ii) develop diagnostic and interventional technologies for early tumor management. Citation Format: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson. Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs [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 B056.
Abstract B020: Charting the cellular heterogeneity of primary and metastatic PDAC microenvironment
Authors: Adrian Blanco-Gomez, Catherine Felton, Antonia Banyard, Claus Jorgensen
Journal: Cancer Research (2024)

Abstract Cancer-associated fibroblasts (CAFs) are important regulators of tumor progression and therapeutic response in PDAC, with several functionally diverse populations now identified. However, while CAF populations with similar transcriptional characteristics have been identified across different tissues, emerging data suggests that these populations may diverge functionally. For example, whereas antigen presenting CAFs (apCAFs) have been suggested to promote immune evasion in PDAC, apCAFs have been associated with anti-tumor immunity in lung cancer. Thus, high resolution mapping of the microenvironment in both primary and metastatic tumors is required to define tissue specific and conserved subsets for functional interrogation. We deployed cytometry by time of flight (CyTOF) to annotate stromal and immune subsets in healthy and tumor bearing murine pancreas, liver and lung. Spatial proximity of tumor and host cells was further annotated using sLP-mCherry, a secreted lipo-permeable form of mCherry. In total, we annotated 50.3 million cells across normal and tumor bearing tissues. Stromal fibroblast populations were highly divergent across both healthy and tumor bearing tissues. Commonly used markers were expressed in a manner dominated by tissue of origin, with less than 10% of fibroblasts and CAFs displaying common phenotypes across tissues. For example, aSMApos/PDGFRalow myCAFs were abundant in lung and liver, Ly6cpos/PDGFRapos/aSMAlow iCAFs were more abundant in the pancreas and MHCIIpos/CD74pos apCAFs were more dominant in lung. In contrast, most immune subsets, with exception of alveolar macrophages and Kupfer cells, were consistently observed across all tissues analysed albeit at different abundances. Tumors arising from epithelial and mesenchymal PDAC cells induce unique changes in CAF subset abundances where epithelial tumors are enriched for myCAFs and mesenchymal tumors induce more apCAFs. These observations were consistent across tumor bearing liver and lung. MyCAFs and PD-L1 or PDL-2 expressing macrophages were generally more proximal to epithelial tumor cells, whereas tumors originating from mesenchymal PDAC cells were enriched for antigen-experienced T cells. Taken together these analyses reveal tissue specific effects on the emerging microenvironment, with shared properties emerging from immune and mesenchymal niche composition. Citation Format: Adrian Blanco-Gomez, Catherine Felton, Antonia Banyard, Claus Jorgensen. Charting the cellular heterogeneity of primary and metastatic PDAC microenvironment [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 B020.
Abstract B049: Pancreatic beta cell stress pathways drive pancreatic ductal adenocarcinoma development in obesity
Authors: Cathy C. Garcia, Aarthi Venkat, Alex Tong, Sherry Agabiti, Lauren Lawres, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar D Muzumdar
Journal: Cancer Research (2024)

Abstract Epidemiologic studies have shown that obesity is a risk factor for more than a dozen cancers, including pancreatic ductal adenocarcinoma (PDAC). As PDAC is one of the leading causes of cancer-related death and obesity rates are rapidly increasing worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. To address this gap in knowledge, our lab combined a well-established genetic model for obesity (O: Lepob/ob) with a Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) that mimics human PDAC progression. Resultant KCO mice had a drastic increase in tumor development compared to their lean counterparts, whereas induced weight loss intercepted tumor progression, showing that the tumor-promoting effects of obesity can be reversed. Bulk RNA sequencing of tumors from these mice revealed aberrantly increased expression of multiple peptide hormones expressed in insulin-producing beta (b) cells of pancreatic islets, including cholecystokinin (CCK) and amylin (Iapp). Strikingly, transgenic expression of CCK and Iapp in b-cells was sufficient to promote Kras-driven pancreatic tumorigenesis in non-obese mice. Single-cell RNA sequencing of b cells showed a trajectory of changes in gene expression with increasing obesity from wildtype to high-fat diet-fed to Lepob/ob mice. Further in silico analysis combining archetypal (AANet) with pseudotime (TrajectoryNet) methods demonstrated that b cells misexpressing hormones (CCK and Iapp) arose from a specific subtype of preexisting b cells, specifically virgin b cells, a rare, immature, regenerative population. Preliminary in vivo lineage tracing analyses in MIP-CreERT;LSL-TdTomato;Lepob/ob mice support these findings. Finally, we investigated the transcriptional networks that lead to aberrant CCK and Iapp expression in b cells. By combining Grainger causality analysis with known gene-gene relationships in the Transcriptional Regulatory Relationship Unraveled by Sentence-based Text mining (TRRUST) v2 database, we discovered a stress-induced mitogen-activated protein kinase (MAPK8)-cJun pathway that promotes pro-tumorigenic hormone expression in b cells. These combined experimental and computational methods nominate novel b cell targets to subvert the development of PDAC, an exocrine tumor. Citation Format: Cathy C. Garcia, Aarthi Venkat, Alex Tong, Sherry Agabiti, Lauren Lawres, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar D Muzumdar. Pancreatic beta cell stress pathways drive pancreatic ductal adenocarcinoma development in obesity [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 B049.
Abstract A077: The EZH2 epigenetic factor orchestrates oncogenic properties in ATM-deficient pancreatic cancer
Authors: Elodie Roger, Anna Härle, Johann Gout, Lukas Perkhofer, Elisabeth Hessmann, Alexander Kleger
Journal: Cancer Research (2024)

Abstract Despite decades of extensive basic and translational research improving our understanding of pancreatic ductal adenocarcinoma (PDAC), its complex biology remains a significant challenge and limits overcoming its dismal prognosis. Due to its resistance to conventional therapies and heterogeneous mutational landscape, molecular stratification and the development of targeted therapeutic options are essential for improving survival of PDAC patients. Previous work from our group investigated loss-of-function mouse models for the serine/threonine kinase ATM causing homologous recombination deficiency (HRD) in PDAC. Specifically, ATM loss caused certain oncogenic features in the arising tumors, including the acquisition of an invasive phenotype along with the emergence of a prominent desmoplastic reaction, but also sensitizes toward platinum-based therapies and PARP1 inhibition (Russell, Nat Commun; Perkhofer, Cancer Res; Gout, Gut). However, the mechanisms orchestrating these oncogenic features remain unclear. Here, we identified the histone-methyltransferase EZH2 as a direct ATM substrate to operate as an epithelial-mesenchymal gatekeeper. In detail, ATM-deficient tumors accumulated EZH2, suggesting that ATM status contributes to rewiring the epigenetic landscape of pancreatic tumors, subsequently supporting oncogenic features. To investigate whether and how EZH2 impacts ATM-deficient PDAC pathogenesis, we generated conditional double ATM and EZH2-knockout in the KrasG12D/+; Ptf1aCre/+ mice. Double-null mice showed extended mouse survival, reduced metastasis burden, and decreased undifferentiated malignant cell features. Interestingly, both in vivo and in vitro investigations revealed that ATM status significantly impacts EZH2 activity via a post-translational regulation axis. Specifically, the ATM kinase activity was critical to promote Culin1 E3-ubiquitin ligase recruitment and subsequent EZH2 ubiquitination and degradation. Finally, we demonstrated that a combinatorial therapy involving a potent EZH2 inhibitor promotes genomic instability and exacerbates the cytotoxic effects of PARP interference in ATM-deficient HRD PDAC. Overall, our study demonstrates that ATM deficiency significantly impacts EZH2 epigenetic functions and pinpoints the molecular stratification according to ATM status prior to pharmacological EZH2 interference in PDAC therapies as a valuable approach to target ATM-deficient HRD tumors. Citation Format: Elodie Roger, Anna Härle, Johann Gout, Lukas Perkhofer, Elisabeth Hessmann, Alexander Kleger. The EZH2 epigenetic factor orchestrates oncogenic properties in ATM-deficient 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 A077.