Abstract 1287: DEC2, a circadian rhythm transcription factor, promotes growth, metastasis and dormancy by facilitating immune cell invasion through decreasing cell surface expression of MHC-1 in a novel model of pancreatic cancer dormancy
Authors: Harris Chris R. , Dudgeon Crissy , Prela Orjola , Wang Lan , Casabianca Anthony , de Menezes Juliana Cazarin , Davidson Christina , Vertino Paula , Altman Brian , Carpizo Darren 
Published: April 2023

Latent recurrence following curative-intent pancreatic cancer surgery is a major clinical problem thought to be due to the reactivation of dormant tumor cells that disseminate before the primary tumor has been removed. How dormancy is established and ultimately reversed to drive recurrence is poorly understood. Here we introduce a novel mouse model of pancreatic cancer dormancy in which we establish distal pancreatic tumors by orthotopic injection, resect them four weeks later and then follow the mice for recurrence. We observed recurrence patterns and survival outcomes that mimic human patients undergoing surgery for pancreatic cancer where two thirds of the mice succumb to early metastatic recurrence (median survival 26 days) and one third of the mice (called dormant mice) live substantially long (median survival 554 days) without clinic evidence of disease yet harbor disseminated tumor cells in most organs of the body. Disseminated tumor cells isolated from the livers of dormant mice were quiescent, exhibited stem cell properties and upregulated the expression of Dec2, a circadian rhythm gene. Overexpression of Dec2 induced quiescence suggesting that it may be a driver of the dormant phenotype. Curiously, endogenous Dec2 actually increased the growth and metastasis of nondormant tumors. Dec2WT and Dec2 knockout cell lines were used to generate resectable orthotopic tumors in immune-competent mice, and loss of Dec2 decreased tumor growth, dissemination and metastasis, and the median survival of mice with DecWT tumors was 25 days whereas 70% of the mice with the otherwise isogenic Dec2KOs were still alive after 200 days. Notably, these differences in tumor size, dissemination, metastasis and survival were abrogated in nude mice, indicating an immune mediated mechanism. Dec2WT and Dec2KO cell lines expressed the same total amount of the antigen-presenting protein MHC-1, but much more of the MHC-1 was present on the surface of Dec2KO cell lines than on the Dec2WT cell lines. MHC-1 requires peptide loading before transport to the cell surface, and we see evidence for reduced production of small peptides in the DecKO cells. For instance the half-life of luciferase, a very potent immunogen in mice, was reduced in the Dec2KO cells, potentially providing small peptides for MHC-1 biosynthesis. Protein turnover may be upregulated to compensate for increases in translation, as ribosomal genes are more highly expressed in Dec2KO cells, including many c-Myc pathway genes. Indeed, Western blot analysis revealed upregulation of c-Myc protein in Dec2KO cells. These data suggest that Dec2 plays a novel role in the immune system by decreasing MHC-1 cell surface expression through decreasing peptide generation, protein translation and turnover.

Citation Format: Chris R. Harris, Crissy Dudgeon, Orjola Prela, Lan Wang, Anthony Casabianca, Juliana Cazarin de Menezes, Christina Davidson, Paula Vertino, Brian Altman, Darren Carpizo. DEC2, a circadian rhythm transcription factor, promotes growth, metastasis and dormancy by facilitating immune cell invasion through decreasing cell surface expression of MHC-1 in a novel model of pancreatic cancer dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1287.