Abstract A115: Collective invasion facilitates liver metastasis in pancreatic ductal adenocarcinoma

Abstract

Abstract Fifty percent of PDAC patients present with distant metastasis and face a dismal prognosis of 8 to 11 months. However, patients with lung metastases have better prognosis than patients with metastatic spread to other sites. In our PDAC metastasis cohort, patients with lung-only metastasis survived longer than patients with liver metastasis, despite sharing the same tumor subtype. To understand features of the primary tumor linked to metastatic site, we generated a novel gene signature for primary organotropism (pORG) that distinguishes primary tumors that developed liver metastasis from those that developed lung metastasis, independent of known tumor subtypes. Our pORG signature predicts survival independently of transcriptional subtype, genetic alterations and clinicopathological variables and in a validation cohort consisting of TCGA pancreatic cancer. Primary tumors with high pORG scores, i.e., liver-tropic primaries, have increased transcriptomic signatures of proliferation and replication stress whereas low pORG tumors have increased lymphocyte gene expression. To validate our findings, we generated cyclic immunofluorescence multiplex imaging data from 34 primary tumors. As anticipated, single cell image analysis revealed high B and T cell infiltration in low-pORG tumors, and increased proliferation and replication stress foci in high-pORG tumors. Intriguingly, malignant cells from high pORG tumors had an increased fraction KRT19-high tumor cells relative to low pORG tumors and were distinctly epithelial in appearance. To reconcile the metastatic behavior of high pORG tumors with their apparent enrichment for epithelial-state cells, we hypothesized that liver-tropism was associated with a partial epithelial-to-mesenchymal transition (EMT) state and metastasis via collective invasion. Bulk transcriptional analysis of 200 PDAC primary tumors revealed a distinct subset of high pORG tumors have increased expression of markers linked to partial EMT and collective invasion, including RAB11a, Rho-like GTPases, and proteases MMP7 and KLK7. Our results support a model of E-cadherin internalization facilitating partial EMT and collective invasion. Current efforts include in-vitro characterization of migration modes in patient-derived cell lines and organoids. Our work suggests unique and targetable tumor intrinsic features linked to organotropism in PDAC. Citation Format: Jennifer R. Eng, Carl Pelz, Koei Chin, Sam Sivagnanam, Link M. Jason, Dove Keith, Lisa Coussens, Rosalie C. Sears. Collective invasion facilitates liver metastasis in pancreatic ductal adenocarcinoma [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 A115.