Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer patients

• Published in: Carcinogenesis (New York) Vol. 43; no. 12; pp. 1198 - 1210
• Main Authors: Yang, Shouhui, Tang, Wei, Azizian, Azadeh, Gaedcke, Jochen, Ströbel, Philipp, Wang, Limin, Cawley, Helen, Ohara, Yuuki, Valenzuela, Paloma, Zhang, Lin, Lal, Trisha, Sinha, Sanju, Rupin, Eythan, Hanna, Nader, Ghadimi, B Michael, Hussain, S Perwez
• Format: Journal Article
• Language: English
• Published: England 31-12-2022
• Subjects: Animals; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Clusterin - genetics; Clusterin - metabolism; Disease Progression; Epithelial-Mesenchymal Transition - genetics; Gemcitabine; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte Nuclear Factor 1-beta - metabolism; Humans; Mice; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgac092

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcomes. We used a strategy of examining the tumors from a subset of PDAC patient cohorts with the worst survival to understand the underlying mechanisms of aggressive disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering, using gene expression profile, revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival, predicted prognosis and stratified patients with significantly different survival in the test and validation cohorts. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of Clusterin (CLU) in the most aggressive patient subset in our patient cohort. Hepatocyte nuclear factor 1 b (HNF1B) positively regulated CLU, and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, 3D spheroid growth, invasiveness and epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines. Mechanistically, CLU enhanced proteasomal degradation of EMT-regulator, ZEB1. In addition, orthotopic transplant of CLU-expressing pancreatic cancer cells reduced tumor growth in mice. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells representing aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, HNF1B/CLU axis negatively regulates pancreatic cancer progression and may potentially be useful in designing novel strategies to attenuate disease progression in PDAC patients.