Abstract C102: Investigating rapid metastatic recurrence of pancreatic cancer after resection in a novel, immune-competent, Myc-dependent murine model
Authors: Phipps Jackie L. , English Isabel , Chu Jennifer , Garza Gustavo Salgado , Link Jason , Langer Ellen , Tsuda Motoyuki , MacPherson Kevin , Pelz Carl , Brody Jonathan , Sheppard Brett , Sears Rosalie , Worth Patrick 
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a median survival time of 10-12 months and an overall 5-year survival rate of 12%. Current treatment includes chemotherapy and surgery; however, only 20% of patients are eligible for resection due to the majority presenting with locally advanced or metastatic disease. Alarmingly, 20-30% of patients who undergo resection of their primary tumor experience rapid liver metastasis within 6 months of surgery. This “rapid recurrence” (rrPDAc) is devastating and poorly understood, contributing to the nihilism surrounding pancreatic cancer. Whether rapid metastases seed before surgery, or surgery results in seeding is unknown. We hypothesize both cases would be affected by systemic and microenvironmental changes that occur due to surgical intervention. In RNA-seq of human rrPDAc primary tumors, we identified increased expression of MYC-targets when compared to those who recurred 18 months or later after surgery (LTR). Cyclic immunofluorescence of primary tumors revealed increased pS62-Myc, replication stress, and DNA damage repair in rrPDAC compared to LTR primary tumors. Furthermore, we identified differences in the tumor immune microenvironments between rrPDAC and LTR, in the absence of substantial clinical differences. To study this phenomenon, we developed an immune competent mouse model of 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 disease progression and are liver metastatic. Considering the role MYC plays in regulation of the immune microenvironment, we hypothesized cell 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 are then randomized into anesthesia only control, sham operation, and tumor resection groups and tracked via twice-weekly trans-abdominal ultrasound. Mice that undergo surgical tumor resection develop liver metastases 11 days earlier than anesthesia only controls (p &lt;0.0001) and sham mice developed liver metastases 10 days earlier than controls (p=0.02, suggesting that surgical intervention perturbs the development of metastatic lesions. This model will allow for investigation into rrPDAc and the role surgery may play in exacerbation of metastasis.

Citation Format: Jackie L. Phipps, Isabel English, Jennifer Chu, Gustavo Salgado Garza, Jason Link, Ellen Langer, Motoyuki Tsuda, Kevin MacPherson, Carl Pelz, Jonathan Brody, Brett Sheppard, Rosalie Sears, Patrick Worth. Investigating rapid metastatic recurrence of pancreatic cancer after resection in a novel, immune-competent, Myc-dependent murine model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C102.