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Pancreatic ductal adenocarcinoma lethality can be attributed to a combination of rapid metastatic dissemination and intrinsic resistance to conventional therapies. Our prior studies using single cell RNA-seq in pancreatic circulating tumor cells (CTCs) revealed that these “seeds of metastasis” had a biphenotypic state of both epithelial and mesenchymal features. This suggested that CTCs are highly plastic cells that exist in an intermediate state along epithelial (E) to mesenchymal (M) transition (EMT). Analysis of CTC markers in primary PDAC tumors revealed that this subpopulation of cancer cells was concentrated at the interface of tumor cells and stromal cancer associated fibroblasts (CAFs). To evaluate the contribution of CAFs in PDAC EMT plasticity, we utilized patient derived PDAC-CAF co-culture preclinical models demonstrating that PDAC EMT heterogeneity was modulated by the density of CAFs and partially driven by TGF-b secretion. Moreover, analysis of patient derived PDAC tumor spheres treated with FOLFIRINOX (FFX) demonstrated selection or induction of EMT changes that were also found in patient tumors that were resected after neoadjuvant FFX. Altogether, our collective work along with others demonstrates the importance of EMT plasticity in PDAC cell metastatic propensity and the ability to resist cytotoxic chemotherapy. A multi-institutional randomized Phase II trial supported by SU2C-Lustgarten Foundation evaluating the role of the TGF-b modulating activities of losartan on locally advanced PDAC response to chemotherapy and suppression of metastatic dissemination has neared completion. This 3 arm (n=40 per arm) trial of neoadjuvant FFX, FFX + losartan, or FFX+ losartan + nivolumab (anti-PD1). Here, we have performed EMT RNA in situ hybridization in all post-treatment resection specimens to determine if there is a difference in EMT proportions between the different arms of the study. As an orthogonal unbiased approach, we have utilized the NanoString GeoMx Digital Spatial Profiler whole transcriptome assay (18,000+ protein coding genes) on each of the resection specimens with analysis of the tumor cells, CAFs, and immune cell separately for multiple regions of interest in these specimens. This provides deeper molecular insight of the PDAC tumor cells that resisted neoadjuvant therapy, the changes in the surrounding CAFs, and the modulation of immune infiltrates that might differ between each arm of the study. We anticipate the results of the trial will be completed before the conference and initial correlative analysis of spatial transcriptomics and RNA-ISH will be presented. Citation Format: Amaya Pankaj, Michael J. Raabe, Bidish Patel, Evan R. Lang, Joshua Kocher, Katherine H. Xu, Linda T. Nieman, Alec C. Kimmelman, David P. Ryan, Theodore S. Hong, William L. Hwang, Martin Aryee, David T. Ting. Characterizing the effects of neoadjuvant therapy in PDAC [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 PR004. |
