HPB
Anthony S. Casabianca, MD
General Surgery Resident
University of Rochester
Rochester, New York, United States
Disclosure: Disclosure information not submitted.
Recurrence following surgery for pancreatic ductal adenocarcinoma (PDAC) is a near universal event. While most patients recur within 24 months, many patients recur years after surgery indicating they harbor dormant disseminated tumor cells (dDTCs). Currently no murine PDAC models recapitulate this biology and as a result pancreatic cancer dormancy remains poorly understood.
Methods:
A model of resectable PDAC was constructed by orthotopic implantation of murine PDAC cells into FVB hosts. Primary tumors are later resected, and recurrence monitored by bioluminescence imaging. dDTCs’ harvested from mice without recurrence underwent transcriptomic profiling using single cell RNA sequencing. Dec2’s contribution to dormancy was evaluated by overexpression and CRISPR knockout.
Results: Overall survival in the mouse model mirrored 41,552 stage I, II National Cancer Database PDAC patients. Distribution of early vs. latent recurrent mice reflected early (median survival 0.8yrs) vs. latent recurrent (median 6yrs) patients with similar frequency and location. Transcriptomic profiling of dDTCs revealed a quiescent state, downregulated proliferation markers, and upregulated genes for immune modulation, cell stemness, linoleic acid (LA) metabolism, and Dec2. We confirmed upregulation of cancer stem cell markers by flow cytometry. dDTCs were resistant to chemotherapy. An in vitro model of dormancy was constructed by LA treatment which decreased cell viability and increased Dec2. Dec2 overexpression induced quiescence, and knockout increases apoptosis upon treatment with LA. Dec2-KO cells implanted in the resection model reduced recurrence with 70% long term survivors ( >100 days) and significantly fewer dDTC's in harvested liver tissue.
Conclusions:
This is the first murine model of pancreatic cancer dormancy that recapitulates outcomes of resected patients. These studies reveal pancreatic cancer dormancy is characterized by a distinct but plastic cellular state characterized by chemotherapy resistance. Dec2 appears required for dormancy. Its absence leads cells to undergo cell death instead of dormancy suggesting Dec2 may be a therapeutic target in pancreatic cancer dormancy.