Abstract B022: Understanding the coordination between EMT and HNF1A in maintaining stemness and promoting metastasis in PDAC
Authors: Crawford Katherine , Abel Ethan V 
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with a dismal 5-year survival rate of only 11%. This is largely because the majority of patients have distant metastases at time of diagnosis. Unfortunately, harsh chemotherapy regimens are the only treatment option for metastatic patients and only extend survival marginally. Further highlighting the aggressiveness of metastatic PDAC, over 80% of patients that receive primary tumor resection will succumb to the disease due to metastatic relapse within five years. Therefore, there is a critical need for identification of viable targets in metastatic PDAC. Epithelial-to-mesenchymal transition (EMT) is a process associated with metastasis that depletes cells of epithelial characteristics, while endowing them with mesenchymal features, including invasiveness. EMT enriches stem cell-like properties giving rise to cancer stem cells (CSCs), a subpopulation of tumor cells that are highly migratory and capable of initiating tumors. The process of EMT is a spectrum generating hybrid intermediate cell states displaying varying degrees of epithelial and mesenchymal features, and stemness is most enriched in intermediate epithelial/mesenchymal cells. Because of their tumorigenic properties, CSCs are known to contribute to metastatic spread, making them prime candidates for the treatment of metastatic PDAC. However, agents targeting CSCs are often met with severe toxicities and/or lack of efficacy, making the discovery of targetable pathways imperative. Previous studies have demonstrated that the transcription factor HNF1A is a key mediator of stem-like properties in PDAC. Interestingly, cells that exhibit intermediate epithelial/mesenchymal features also display the highest HNF1A expression and stemness. Moreover, data show that loss of HNF1A shifts cells to an epithelial state and strong EMT induction via EMT transcription factor overexpression also represses HNF1A and stemness, suggesting an interplay between HNF1A and EMT. Preliminary data further indicates that HNF1A overexpression significantly promotes cell migration and invasion while knockdown of HNF1A significantly reduces migration, supporting a role for HNF1A in PDAC metastasis. Because HNF1A is not currently targetable, FGFR4 was identified as a druggable HNF1A target gene via RNA-sequencing. Data show that knockdown of FGFR4 significantly reduces HNF1A-mediated cell migration. Overall, these data support the hypothesis that HNF1A maintains PDAC cells in an intermediate epithelial/mesenchymal state with high stemness and metastatic potential. Additionally, inhibition of the downstream effector, FGFR4, may be a mechanism to overcome metastatic spread in PDAC.

Citation Format: Katherine Crawford, Ethan V Abel. Understanding the coordination between EMT and HNF1A in maintaining stemness and promoting metastasis in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B022.