Bermejo-Rodriguez, Camino, Araos Henríquez, Joaquín, Caligiuri, Giuseppina, Pinto Teles, Sara, Park, Youngkyu, Evans, Anthony, Barrera, Lawrence N, Neesse, Albrecht, Grutzmann, Robert, Aust, Daniela, Rümmele, Petra, Knösel, Thomas, Narita, Masako, Narita, Masashi, Campbell, Fiona, Öhlund, Daniel, Pilarsky, Christian, Dow, Lukas E, Humbert, Patrick O, Biffi, Giulia, Tuveson, David A, Perez-Mancera, Pedro A (July 2024) Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis. Cancer Research. ISSN 0008-5472 (Public Dataset)
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 on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) 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 cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Tuveson lab CSHL Cancer Center Program |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 22 July 2024 |
| Date Deposited: | 29 Jul 2024 13:19 |
| Last Modified: | 29 Jul 2024 13:19 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/41625 |
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