Abstract The mechanisms that regulate tumor progression and dormancy in pancreatic adenocarcinoma (PDAC) remain poorly understood. We established a murine model of early-stage PDAC that recapitulates the overall survival and metastatic recurrence patterns of patients. We isolated disseminated tumor cells (DTCs) from the livers of latent recurrent mice and found them with characteristics of dormant cells. Transcriptomic analysis indicated that not only were these cells quiescent (Ki67lo) relative to primary tumor cells, but they also exhibited high levels of the transcriptional repressor Dec2. We validated this finding in human PDAC on liver tissues from patients with stage IV disease demonstrating that isolated small clusters of DTCs were more likely Dec2hi/Ki67lo, than tumor cells in established metastases. Compared to normal pancreas, Dec2 levels are increased in PDAC tumor, and we could detect Dec2 in proliferating PDAC cells (though not at the levels as seen in dormant DTC), suggesting that Dec2 plays a role in PDAC biology beyond dormancy. We generated Dec2 knock out (KO) in murine PDAC cells for orthotopic and liver metastasis models. Loss of Dec2 markedly inhibited tumor progression and metastasis that was dependent on adaptive immune system, as the effect was abrogated when either nude hosts were used, or immunocompetent hosts were subjected to anti-CD4 and CD8 depletion. We further found that Dec2 KO cells had increased surface MHC-I as well as total MHC-I. CUT Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A014.
Wang et al. (2025) studied this question.