SURGERY ACCELERATES PANCREATIC LIVER METASTASIS IN AN IMMUNE COMPETENT MOUSE MODEL
Jackie L. Phipps*, Isabel A. English, Jennifer M. Chu, Motoyuki Tsuda, Kevin A. MacPherson, Colin J. Daniel, Carl Pelz, Jonathan Brody, Brett C. Sheppard, Rosalie Sears, Patrick J. Worth
Oregon Health & Science University, Portland, OR
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 accelerated by systemic and microenvironmental changes due to surgical intervention.
In RNA-seq of human rrPDAC primary tumors, we identified increased expression of Myc-targets when compared to long-term non-recurrers (no metastasis 18 months after surgery). 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=24), distal pancreatectomy (n=17), and sham laparotomy cohort (n=11) and metastases were tracked via ultrasound twice-weekly. Surgically resected mice developed liver metastases 11 days earlier than controls (p <0.0001) and sham surgery mice developed liver metastases 10 days earlier than controls (p=0.02).
In the rrPDAC KMC model, RNA-sequencing of liver parenchyma of mice one day after surgery showed significantly elevated levels of Saa1/2 mRNA compared to nonoperative controls. Saa1/2 is indicative of a systemic inflammatory response after surgery, and Saa1/2 have previously been reported to contribute to the pre-metastatic niche development in pancreatic cancer (1), but this was reported in the context of normal PDAC development, not in a surgical setting. We hypothesize the systemic inflammatory response and corresponding increase in Saa1/2 after surgery primes the liver for metastatic outgrowth.
This model will allow for investigation into rrPDAC and the role surgery plays in exacerbation of metastasis in humans.
Lee J et al. Serum Amyloid A Proteins and Their Impact on Metastasis and Immune Biology in Cancer. Cancers (Basel). 2021 Jun 25;13(13):3179.
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