Abstract A007: Spatial Single-Cell Multi-Omics Identifies Niche Modulated MIC-to-MCC Plasticity Underlying Pancreatic Cancer Hepatic Metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) confers dismal clinical outcomes largely owing to its robust metastatic propensity, among which liver metastasis accounts for the deadliest metastatic phenotype. The core malignant cell populations governing the onset and outgrowth of PDAC hepatic metastasis, as well as their spatiotemporal crosstalk with local microenvironments, remain poorly characterized. Herein, we combined spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) to systematically profile paired primary PDAC lesions and matched liver metastases, mapping their distinct cell subpopulations and spatially resolved transcriptional landscapes, with cross-cohort dataset validation. We uncovered two functionally distinct tumor cell subsets: metastasis-initiating cells (MICs) enriched in primary tumors and metastatic colonizing cells (MCCs) predominant in hepatic metastatic lesions, and delineated a linear MIC-to-MCC developmental trajectory orchestrated by PI3K-STAT2-mediated cholesterol metabolic reprogramming. This phenotypic transition was further shaped by TIMP1-expressing myofibroblastic cancer-associated fibroblasts within the liver metastatic niche. Functional knockdown of the signature marker for MICs drastically suppressed PDAC metastatic potential in vitro, verifying the indispensable role of MIC subpopulation in fueling liver metastasis. Collectively, our work refines the mechanistic framework of PDAC hepatic dissemination and provides actionable therapeutic targets to block metastatic progression in solid malignancies.