Abstract 1245: A novel, immune-competent, Myc-dependent model of rapid metastatic recurrence of pancreatic cancer after resection

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a resistant malignancy with dismal outcomes. Early diagnosis, systemic treatment, and surgical resection are interdependently essential in improving survival. However, 20-30% of patients who undergo primary tumor resection will experience a metastatic recurrence in the liver within six months of surgery, despite no substantial differences in clinical history. This “rapid recurrence” (rrPDAC) is poorly understood. These metastatic lesions have a few possible origins, including occult synchronous metastases and disseminated metachronous lesions. We hypothesize metastases from either origin are affected by systemic and microenvironmental changes due to surgical intervention. RNA-seq of human rrPDAC primary tumors identified increased expression of Myc-targets when compared to long-term non-recurrers. Here, we describe a novel mouse model of immune competent, surgically resected PDAC that models rapid recurrence. Utilizing novel cell lines derived from our lab’s inducible, p48-Cre-recombinase driven LSL-KrasG12D/+ LSL-ROSA-MYC+/+ (KMC) mouse model, we orthotopically implanted KMC tumor cells into the pancreas of immune competent mice and monitored tumor growth and liver metastases weekly for two weeks via ultrasound. Mice taken down at day 14 (pre-surgery) did not demonstrate micrometastases on serial liver sectioning, however circulating tumor cells were present and isolated from venous blood. Experimental mice were randomized into control (n=17), distal pancreatectomy (n=14), and sham laparotomy cohort (n=14) and metastases were tracked via ultrasound twice-weekly. Surgically resected and sham surgery mice developed liver metastases a median 12 days earlier than controls. Additionally, using cell lines derived from the more traditionally studied KPC mouse model of PDAC (Kras activating mutation and p53 loss of function mutation) and the surgical model described above, distal pancreatectomy (n=13) resulted in metastasis to the liver in a median of 9 days earlier than controls (n=12).In the rrPDAC KMC model, RNA-sequencing of liver parenchyma of mice one day after surgery showed significantly elevated levels of Saa1 mRNA compared to nonoperative controls. This is indicative of a systemic inflammatory response after surgery that we hypothesize is having pro-metastatic effects on the liver, which has been previously reported (1).This model will allow for investigation into rrPDAC and the role surgery plays in exacerbation of metastasis in humans. Our goal is to inform changes in pre- and/or post-operative standards of care for pancreatic resection surgery to reduce the risk of rapid liver metastasis following pancreas resection surgery.