Giant obscurin regulates migration and metastasis via RhoA-dependent cytoskeletal remodeling in pancreatic cancer. (1st February 2022)

• Record Type: Journal Article
• Authors: Tuntithavornwat, Soontorn; Shea, Daniel J.; Wong, Bin Sheng; Guardia, Talia; Lee, Se Jong; Yankaskas, Christopher L.; Zheng, Lei; Kontrogianni-Konstantopoulos, Aikaterini; Konstantopoulos, Konstantinos
• Is Part Of: Cancer letters. Volume 526(2022)
• Page Start: 155
• Page End: 167
• Publication Date: 2022-02-01
• Subjects: Cytoskeleton -- Migration -- Metastasis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.11.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Obscurins, encoded by the OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. Large scale omics analyses reveal that OBSCN is highly mutated across different types of cancer, exhibiting a 5–8% mutation frequency in pancreatic cancer. Yet, the functional role of OBSCN in pancreatic cancer progression and metastasis has to be delineated. We herein show that giant obscurins are highly expressed in normal pancreatic tissues, but their levels are markedly reduced in pancreatic ductal adenocarcinomas. Silencing of giant obscurins in non-tumorigenic H uman P ancreatic D uctal E pithelial (HPDE) cells and obscurin-expressing Panc5.04 pancreatic cancer cells induces an elongated, spindle-like morphology and faster cell migration via cytoskeletal remodeling. Specifically, depletion of giant obscurins downregulates RhoA activity, which in turn results in reduced focal adhesion density, increased microtubule growth rate and faster actin dynamics. Although OBSCN knockdown is not sufficient to induce de novo tumorigenesis, it potentiates tumor growth in a subcutaneous implantation model and exacerbates metastasis in a hemispleen murine model of pancreatic cancer metastasis, thereby shortening survival. Collectively, these findings reveal a critical role of giant obscurins as tumor suppressors in normal pancreatic epithelium whose loss of function induces RhoA-dependent cytoskeletal remodeling, and promotes cell migration, tumor growth and metastasis. Highlights: Obscurin expression is lower in pancreatic ductal adenocarcinoma than normal tissue. OBSCN silencing promotes cell motility via RhoA-dependent cytoskeletal remodeling. OBSCN knockdown is not sufficient to induce de novo tumorigenesis. OBSCN depletion potentiates tumor growth and metastasis in vivo .