TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells

Abstract

Background Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-β, provides possible convenience for the progression of PC cells. TGF-β regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-β-mediated autophagy are still poorly understood. Methods Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-β-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-β-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. Results We demonstrated that TGF-β induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-β regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. Conclusions Our findings reveal TFEB-driven autophagy is required for TGF-β induced migration and metastasis of PC cells by promoting endocytosis of Itgα5β1 and focal adhesion disassembly through the TGF-β-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1343-4) contains supplementary material, which is available to authorized users.

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The Oncogene Transcription Factor EB Regulates Vascular Functions

“…Upregulation of TFEB in several cancers, such as pancreatic adenocarcinoma, melanoma, renal cell carcinoma colorectal cancer and non-small cell lung cancer (Davis et al, 2010;Liang et al, 2010;Giatromanolaki et al, 2015;Li et al, 2019), promotes cancer progression via mTORC1 hyperactivation signaling to promote cell proliferation and boost autophagy, producing an intracellular pool of nutrients, most importantly amino acids, and thus supporting cancer growth. Moreover, in pancreatic cancer, TFEB-induced autophagic activation leads to cancer progression via increased migration and metastasis of cancer cells due to endocytosis of Itgα5 and disassembly of adhesion machinery (He et al, 2018). The autophagyindependent function of TFEB was demonstrated in breast cancer, where TFEB inhibited apoptosis by regulating DNA repair mechanisms (Slade et al, 2020).…”