Abstract B026: Surgery accelerates metastatic recurrence in a novel, immune-competent mouse model of resectable pancreatic cancer
Authors: Phipps Jackie L. , English Isabel A. , Chu Jennifer M. , Tsuda Motoyuki , Pelz Carl , Daniel Colin , Keith Dove , Sheppard Brett C. , Brody Jonathan , Sears Rosalie C , Worth Patrick J. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAc) remains a resistant malignancy with dismal outcomes. Early diagnosis, systemic treatment, and complete resection are interdependently essential in improving survival. But even with these, 20-30% of patients will experience a metastatic recurrence within six months of surgery. This “rapid recurrence” (rrPDAc) is devastating and poorly understood and contributes to the nihilism surrounding pancreatic cancer. Overlapping etiologies of these metastatic lesions are possible. They include occult synchronous metastases, as well as disseminated metachronous lesions, both of which we hypothesize may be affected by systemic and microenvironmental changes that occur due to surgical intervention. In human rrPDAc primary tumors, we have identified increased expression of Myc-targets and differences in tumor immune microenvironment when compared to long-term non-recurrers, in the absence of substantial clinical differences in the cohorts, supporting the hypothesis that cell-intrinsic, biological differences exist in patients who undergo rapid recurrence. Furthermore, we have demonstrated in a clinical cohort that this effect persists in spite of neoadjuvant or adjuvant therapy, and is promoted by postoperative surgical site infections. Here, we describe a novel mouse model of immune competent, surgically resected PDAc that models rapid recurrence compared to control mice. Utilizing novel cell lines derived from our lab’s inducible, p48-Cre-recombinase driven LSL-KrasG12D/+ LSL-ROSA-MYC+/+ mouse model, we orthotopically implanted 25,000 cells into the tail of F1-generation BL/6-129J mice and monitored growth and identifiable liver metastases via trans-abdominal ultrasound weekly for two weeks. Mice taken down at day 14 (‘pre-op’ cohort) did not demonstrate micrometastases on serial liver sectioning, however circulating tumor cells (EpCAM+ CD45-) cells were present in venous blood. Experimental mice were then randomized into control (anesthesia only, n = 17), distal pancreatectomy (n = 14), and sham laparotomy cohorts (n = 11). Metastases were tracked via twice-weekly trans-abdominal ultrasound. Surgically resected and sham surgery mice developed metastases a median 12 days earlier than controls (p = 0.003), suggesting that surgical intervention promotes and accelerates the development of metastatic lesions. Furthermore, we have demonstrated that circulating tumor cells may be isolated from the portal venous drainage of these mice, allowing for a novel resource in studying pre-, intra-, and metastatic-compartments of tumor. Through this model we are able to access early metastatic lesions not obtainable in human subjects. Furthermore we can utilize this model to probe the effects of surgical intervention and the immune system on metastasis. This model will allow for investigation into rrPDAc and the role surgery may play in exacerbation of metastasis in humans with an eye towards developing targeted translational investigations.
Citation Format: Jackie L. Phipps, Isabel A. English, Jennifer M. Chu, Motoyuki Tsuda, Carl Pelz, Colin Daniel, Dove Keith, Brett C. Sheppard, Jonathan Brody, Rosalie C Sears, Patrick J. Worth. Surgery accelerates metastatic recurrence in a novel, immune-competent mouse model of resectable pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B026.