Cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma

Some patients with localized pancreatic ductal adenocarcinoma (PDAC) undergo resection with curative intent, but most experience disease recurrence and succumb to their disease. Through examination of 743 PDAC patients in a single-center we find that the site of first recurrence is a major predictor of survival. Patients with initial liver-metastatic recurrence (LIV-MR, n = 100) had significantly shorter disease-free and overall survival compared to those with initial recurrence to the lung (LUN-MR, n = 31). We performed single-nucleus RNA-seq (snRNA-seq) and low-pass whole-genome sequencing (lpWGS) on a representative population of this cohort, including 21 primary PDACs with either LIV-MR or LUN-MR, and found that malignant cells adopt transcriptional programs that mimicked that of their ultimate metastatic target organ. We validated the LIV-MR and LUN-MR signatures in multiple data sets, including single-cell RNA-seq of normal human adult and fetal liver and lung tissues, bulk, single-cell, and spatial transcriptomics of PDAC lung and liver metastases, and in vivo data modelling metastatic organotropism in PDAC and other lineages. We reconstructed two different trajectories of malignant transformation in PDAC and find that the LIV-MR and LUN-MR are associated with these, suggesting that subsequent metastatic organotropism may be determined early in tumorigenesis. Furthermore, primary PDAC tumors recurring with LIV-MR compared to LUN-MR were deplete of infiltrating T cells and enriched with M2-like macrophages, highlighting potential contributions to subsequent outcomes. Taken together, this work provides evidence for pre-existing cellular adaptations that determine metastatic organotropism and may be useful for prognostication and development of therapeutic strategies at the time of diagnosis of resectable PDAC. Single-nucleus RNA sequencing of 91,872 nuclei from 21 primary PDAC specimens, including 8 from patients with subsequent liver- and 13 with lung-metastatic recurrence. Out of 21 patients, 4 received neoadjuvant therapy and the rest were treatment-naïve.