1. Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.
- Author
-
Bermejo-Rodriguez C, Araos Henríquez J, Caligiuri G, Pinto Teles S, Park Y, Evans A, Barrera LN, Neesse A, Grützmann R, Aust D, Rümmele P, Knösel T, Narita M, Narita M, Campbell F, Öhlund D, Pilarsky C, Dow LE, Humbert PO, Biffi G, Tuveson DA, and Perez-Mancera PA
- Subjects
- Animals, Mice, Humans, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Cell Line, Tumor, Membrane Proteins genetics, Membrane Proteins metabolism, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Interleukin-1alpha metabolism, Interleukin-1alpha genetics, Organoids metabolism, Organoids pathology, Mice, Knockout, Neoplasm Metastasis, Gene Expression Regulation, Neoplastic, Tumor Microenvironment, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins deficiency, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism
- Abstract
Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well-characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency in PDAC development and progression, Scrib expression was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and an abundance of cancer-associated fibroblasts (CAF). Mechanistically, IL1α levels were reduced in Scrib-deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDO), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer. Significance: SCRIB loss promotes invasive pancreatic cancer development via both cell-autonomous and non-cell-autonomous processes and is associated with poorer outcomes, denoting SCRIB as a tumor suppressor and potential biomarker for the prediction of recurrence., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF