Abstract A031: Molecular basis of MYC-driven basal-squamous pancreatic cancer evolution

Abstract

Basal-squamous pancreatic ductal adenocarcinoma (PDAC) is the most aggressive molecular subtype, yet the mechanisms underlying its emergence remain poorly understood. Using the Msi2-Myc mouse model, we previously demonstrated that MYC activation in Msi2+ stem-like cells is sufficient to generate basal-squamous PDAC. To define the molecular events underlying this tumorigenesis, we performed single-cell RNA sequencing of Msi2-Myc tumors. Trajectory analysis identified dynamic activation of Ly6/uPAR family members during subtype evolution, with Lypd3 selectively expressed in ΔNp63+ squamous tumor cells. Depletion of Lypd3 in mouse and human basal-squamous PDAC models significantly suppressed tumor growth in vivo. Transcriptomic analysis following Lypd3 depletion demonstrated marked suppression of MYC targets, E2F targets, and cell-cycle pathways. Together, these findings identify LYPD3 as a critical regulator required for basal-squamous tumor growth.