Unveiling FKBP7 as an early endoplasmic reticulum sentinel in pancreatic stellate cell activation, collagen remodeling and tumor progression

Abstract

In pancreatic ductal adenocarcinoma (PDAC), fibroblast activation leads to excessive secretion of extracellular matrix (ECM) and soluble factors that regulate tumor progression, prompting investigation into endoplasmic reticulum (ER)-resident proteins that may support this activation. We identified FKBP7, a peptidyl-prolyl isomerase in the ER, as overexpressed in PDAC stroma compared to cancer cells, and in patients with favorable prognosis. Analysis of single-cell RNA sequencing databases revealed FKBP7 expression in pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs). When analyzed by immunohistochemistry on PDAC patient tissues, FKBP7 emerged as an early activation marker in the preneoplastic stroma, preceding αSMA expression, and responding to FAK- and TGFβ-induced stiffening and pro-fibrotic programs in PSCs. Functional analyses revealed that FKBP7 knockdown in PSCs enhanced contractility, Rho/FAK signaling, and secretion of pro-inflammatory cytokines as well as remodeling of type I collagen, promoting an activated phenotype and accelerating tumor growth in vivo. Conversely, FKBP7 expression supported a tumor-restraining (i.e. encapsulating) ECM characterized by type IV collagen. Mechanistically, FKBP7 interacts with BiP, and blocking this interaction instead leads to increased PSC secretion of type I collagen. Thus, FKBP7 serves as a novel PSC marker and ER regulator in a complex with BiP of the secretion of specific collagen subtypes, highlighting its potential to mediate ECM normalization and constrain PDAC tumorigenesis.