Abstract PR012: A novel, immune-competent, Myc-dependent murine model of rapid metastatic recurrence of pancreatic cancer after resection
Authors: Worth Patrick J. , English Isabel A. , Phipps Jackie M. , Link Jason M. , Langer Ellen M. , Tsuda Motoyuki , Daniel Colin , Pelz Carl , Brody Jonathan , Sheppard Brett C. , Sears Rosalie C. 
Published: January 2023

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 interventions, 20-30% of patients will experience a metastatic recurrence within six months of surgery. This “rapid recurrence” (rrPDAc) is devastating and poorly understood, contributing 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 elements of the tumor immune microenvironment when compared to long-term non-recurrers, in the absence of substantial clinical differences. We describe a novel mouse model of immune competent, surgically resected human PDAc that models rapid recurrence compared to control mice. Our lab has developed an inducible, p48-Cre-recombinase driven LSL-KrasG12D/+ LSL-ROSA-MYC+/+ mouse model that reproducibly develops ADM to PanIN to PDAc lesions that highly recapitulate human carcinogenesis. Lesions lose Smad4 expression progressively, a feature associated with metastatic phenotypes of human PDAc, and also metastasize to the liver. Considering the role MYC plays in regulation of the immune microenvironment, we hypothesized that lines derived from this model would perform well in a model of rapid recurrence. We derived several cell lines from these tumors and implanted them orthotopically in syngeneic mice, monitoring tumor development over fourteen days with ultrasound. Mice were then subjected to takedown (‘pre-op’, n = 5), anesthesia-only controls (n = 17), sham surgical incision (n = 11), and distal pancreatectomy (n = 14). No micro-metastases were identified in livers of the ‘preop’ controls. Mice were tracked via twice-weekly trans-abdominal ultrasound. Surgically resected and sham surgery mice developed metastases a median of 10 days earlier than controls (p = 0.008), suggesting that surgical intervention perturbs 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. This model will allow for investigation into rrPDAc and the role surgery may play in exacerbation of metastasis.

Citation Format: Patrick J. Worth, Isabel A. English, Jackie M. Phipps, Jason M. Link, Ellen M. Langer, Motoyuki Tsuda, Colin Daniel, Carl Pelz, Jonathan Brody, Brett C. Sheppard, Rosalie C. Sears. A novel, immune-competent, Myc-dependent murine model of rapid metastatic recurrence of pancreatic cancer after resection [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR012.