Abstract PO-082: Delineating the molecular basis of early dissemination of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages rendering the already limited therapeutic options ineffective for many patients. Earlier diagnosis permits for “curative” surgery; however, 95% of these patients experience recurrence locally or distally and die within ten years of treatment. One hypothesis that can explain high recurrence is the early dissemination of PDAC progression. At the time of surgery, systemic subclinical dissemination of predominantly dormant cells found ubiquitously within patient livers has already occurred prior to the development of overt metastatic disease or bona fide recurrent PDAC. However, remarkably little is known about early PDAC cell dissemination despite these dismal outcomes, mainly due to the lack of human models to study disease progression. We previously demonstrated the cellular reprogramming “proof-of-principle” to model human PDAC progression (designated “10-22 cells”) and its use as a discovery tool for early biomarkers by unveiling a marker for stage 1 PDAC in human patients. We further analyzed transcriptomes of genetically tagged 10-22 cells progressing from pancreatic intraepithelial neoplasia (PanIN) to PDAC in mice and validated the results using the TCGA PDAC dataset, human clinical PanIN, PDAC tissues, and a well-established murine PDAC model. We found that extracellular vesicle transport and neuronal cell differentiation pathways were derepressed in the progression of PanINs to PDAC. HMG-Box Transcription Factor 1 (HBP1) emerged as a potential master factor regulating dynamically expressed genes in neuronal cell differentiation and dissemination during PDAC progression. HBP1 expression are aberrantly regulated in human and murine PanINs and PDAC tissue samples, and their mRNA expressions are inversely correlated with PDAC patients' prognosis. Ectopic overexpression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells. Conversely, knocking out HBP1 in PDAC cells decreased proliferation and migration. Altogether, our data indicate that HBP1 may confer the cell dissemination capacity in early PDAC progression. We are on the way to further dissect the mechanisms by which HBP1 regulates pancreatic cell migration and confers neuronal migratory phenotypes and how these signaling influence PDAC progression and prognosis. Citation Format: Taelor J. Ekstrom, Dmytro Grygoryev, Terry Morgan, Kenneth S. Zaret, Jungsun Kim. Delineating the molecular basis of early dissemination of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-082.