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.
Related
- Three-dimensional architecture of the endoplasmic reticulum network in soybean roots reveals extensive remodeling during cyst nematode parasitism
- Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances
- Immune cell metabolic reprogramming in pancreatic cancer: roles in tumor progression and therapeutic strategies
- Epigenome Alterations and 3D Chromatin Architecture Remodeling in Inflammatory Macrophage Activation under Diabetic Conditions
- Multi-omics profiling of the choroid plexus reveals developmental cellular remodeling, early immune gene activation, and epithelial cell heterogeneity
BibTeX
@article{quemerais2026unveiling,
title = {{Unveiling FKBP7 as an early endoplasmic reticulum sentinel in pancreatic stellate cell activation, collagen remodeling and tumor progression}},
author = {Christophe Quemerais and Christine Jean and Alexia Brunel and Emilie Decaup and Guillaume Labrousse and Hippolyte Audureau and Jérôme Raffenne and Ismahane Belhabib and Jérôme Cros and Aurélie Perraud and Nelson Dusetti and Remy Nicolle and Muriel Mathonnet and Stéphane Pyronnet and Yvan Martineau and Marjorie Fanjul and Corinne Bousquet},
journal = {Cancer Letters},
year = {2026},
month = oct,
doi = {10.1016/j.canlet.2025.217538},
url = {https://hal.science/hal-05782063v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Unveiling FKBP7 as an early endoplasmic reticulum sentinel in pancreatic stellate cell activation, collagen remodeling and tumor progression
AU - Christophe Quemerais
AU - Christine Jean
AU - Alexia Brunel
AU - Emilie Decaup
AU - Guillaume Labrousse
AU - Hippolyte Audureau
AU - Jérôme Raffenne
AU - Ismahane Belhabib
AU - Jérôme Cros
AU - Aurélie Perraud
AU - Nelson Dusetti
AU - Remy Nicolle
AU - Muriel Mathonnet
AU - Stéphane Pyronnet
AU - Yvan Martineau
AU - Marjorie Fanjul
AU - Corinne Bousquet
PY - 2026
DA - 2026/10/06
JO - Cancer Letters
DO - 10.1016/j.canlet.2025.217538
UR - https://hal.science/hal-05782063v1
AB - 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.
SN - 0304-3835
ER -