Wnt11-induced fibrosis in local and metastatic pancreatic cancer

• Applicant: Dr. Jannis Duhn
• Subject Area: General and Visceral Surgery
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582772859

Pancreatic ductal adenocarcinoma (PDAC) represents the third leading cause of cancer-related mortality worldwide. Its poor prognosis is driven by early local and metastatic dissemination, high recurrence rates even after radical resection, and profound chemoresistance. A key hallmark of PDAC progression is desmoplastic fibrosis, mainly orchestrated by cancer-associated fibroblasts (CAFs). Preliminary work from Dr. Kim’s laboratory (MD Anderson Cancer Center, Houston) identified Wnt11 as a top enriched secreted ligand in murine PDAC models. Genetic ablation of Wnt11 markedly reduced stromal fibrosis and decreased hepatic metastases by >75%. Conversely, Wnt11 overexpression in hepatocytes induced a tenfold increase in collagen deposition and activation of pro-fibrotic genes. Since low-density lipoprotein receptor-related protein 6 (LRP6) mediates canonical Wnt-signaling and drives hepatic fibrosis and carcinogenesis in mice, we hypothesize that tumor-secreted Wnt11 activates local CAFs and hepatic fibroblasts (hCAFs) through LRP6 signaling, constituting a novel pathway promoting fibrosis, chemoresistance, and metastasis in PDAC. The program is structured into two work packages (WPs). WP1 will dissect Wnt11-induced signaling in local CAFs and its impact on chemoresistance. Organoid co-cultures of Wnt11-deficient PDAC cells and CAFs will be generated using an inducible conditional Wnt11 knockout and reporter mouse model (available at the host lab). Multiplex immunohistochemistry, 3D immunofluorescence, and single-cell RNA sequencing (scRNAseq) will delineate pro-fibrotic pathways (WP1a). Pharmacologic inhibition of LRP6 by Niclosamide, alone or combined with Gemcitabine, will assess reversal of fibrosis and effects on chemosensitivity (WP1b). Spatial RNAseq in patient-derived PDAC tissue microarrays (generated at our home lab) will correlate WNT11 expression with fibrosis and clinical outcomes (WP1c). WP2 will define mechanisms of Wnt11-driven hepatic fibrosis during metastasis. Conditional Wnt11 knockout will be induced after liver metastasis formation, to isolate hCAFs for organoid coculture and scRNAseq profiling of pro-fibrotic pathways (WP2a). LRP6 inhibition by Niclosamide will be evaluated for anti-fibrotic and chemosensitizing effects in the metastatic setting (WP2b). Finally, transcriptional reprogramming linked to WNT11 will be identified using publicly available spatial RNAseq datasets of human PDAC liver metastases and matched primary tumors (WP2c). This 24-month project aims to uncover Wnt11-LRP6-driven fibroblast activation as a central mechanism of PDAC fibrosis and metastasis, providing novel therapeutic targets to overcome chemoresistance and improve patient outcomes. Integration into the host lab’s expertise in PDAC biology and metastasis ensures optimal feasibility and high-impact translational outcomes.

• DFG Programme: Fellowship
• International Connection: USA
• Host: Professor Dr. Michael Kim