Abstract
Abstract Many tumor types, including pancreatic adenocarcinomas, have dysregulated circadian rhythms. Here we show that the master regulator of circadian control, BMAL1, is overexpressed in pancreatic ductal adenocarcinoma (PDAC) relative to normal tissue and plays a role in protecting PDAC cells from recognition by the immune system. Using CRISPR-generated knockout (KO) cell lines, we evaluated the cells ability to create liver metastasis using a splenic metastasis assay and found that loss of Bmal1 KO abrograted metastasis. We hypothesized that could be through an immune mediated mechanism and evaluated the Bmal KO cells for their expression of cell surface MHCI. Remarkably loss of Bmal1 led to a significant increase in cell surface MHCI expression. This was due to a change in localization of the MHCI molecule. Proper localization of MHC1 is known to depend upon proteasome-generated peptides, and we found that loss of Bmal1 increased proteosomal activity. We used Cut and Run to demonstrate that Bmal1 binds directly to the promoters for core components of the proteosome. Taken together these studies implicate Bmal1 in regulating anti-tumor immunity in PDAC through its regulation of protesomal activity and MHC1 surface expression. This is a novel function for a circadian rhythm gene in PDAC biology. Citation Format: Orjola Prela, Lan Wang, Ching-Hua Shih, Juliana Cazarin de Menezes, Brian Altman, Paula M. Vertino, Chris R. Harris, Darren R. Carpizo. The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas by reducing proteasome activity and MHC1 cell surface localization [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 C019.
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