The circadian rythem genes Dec2 and Bmal1 promote cancer dormancy by facilitating immune evasion
Metastatic recurrence following curative-intent pancreatic cancer (PC) surgery is a major clinical problem as nearly all die of this at both early and latent periods following surgery. Latent recurrences are due to reactivation of dormant tumor cells that disseminate before the primary tumor has been removed. The mechanisms that drive cancer dormancy are poorly understood in part because of the lack of animal models that recapitulate the biology of the resected patient.
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 PC 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 clinical 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. Deletion of Dec2 in the PC cells led to a striking improvement in survival due to the eradication of disseminated tumor cells. The mechanism of this was immune mediated and due to a dramatic upregulation of cell surface MHCI. The increase in cell surface MHCI was due to enhanced localization of the protein as both total MHC1 mRNA and MHC1 protein were unchanged between Dec2 WT and KO cells. Proper localization of MHC1 is known to depend upon proteasome-generated peptides, and mechanistic studies revealed that Dec2 loss increased proteosomal activity and upregulated a number of proteosomal genes. Dec2 bound directly to the promoters of proteosomal genes and moreover directed binding of a second protein, Bmal1, the master regulator of circadian rhythm. Loss of Dec2 led to dramatic reduction in Bmal1 occupancy sites, including sites on proteosomal gene promoters. We deleted Bmal1 from PC cells and found it phenocopied the Dec2 KO cells in that proteosomal activity and surface MHCI expression both increased, and liver metastasis was significantly abrogated.
Taken together these studies describe a new mechanism for Dec2/Bmal1 in regulating tumor progression and dormancy through its regulation of proteosomal activity and cell surface MHCI. Furthermore, this is the first study to implicate circadian rhythm genes as regulators of cancer dormancy and identifies them as potential therapeutic targets.
A novel model of early-stage resectable pancreas cancer that mirrors human outcomes.