PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis

Tian-Yi Jiang; Yuan-Yuan Shi; Xiao-Wen Cui; Yu-Fei Pan; Yun-Kai Lin; Xiao-Fan Feng; Zhi-Wen Ding; Chun Yang; Ye-Xiong Tan; Li-Wei Dong; Hong-Yang Wang

doi:10.1053/j.gastro.2022.11.025

PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis

Gastroenterology. 2023 Mar;164(3):424-438. doi: 10.1053/j.gastro.2022.11.025. Epub 2022 Nov 25.

Authors

Tian-Yi Jiang¹, Yuan-Yuan Shi², Xiao-Wen Cui³, Yu-Fei Pan⁴, Yun-Kai Lin¹, Xiao-Fan Feng⁴, Zhi-Wen Ding⁵, Chun Yang⁶, Ye-Xiong Tan⁷, Li-Wei Dong⁸, Hong-Yang Wang⁹

Affiliations

¹ National Center for Liver Cancer, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai, China.
² National Center for Liver Cancer, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; The First Affiliated Hospital of Naval Medical University, Shanghai, China.
³ National Center for Liver Cancer, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; Department of Oncology, Eastern Hepatobiliary Surgery Hospital, the Naval Military Medical University, Shanghai, China.
⁴ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai, China.
⁵ Department of Surgery, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai, China.
⁶ Children's Hospital of Soochow University, Suzhou, P. R. China.
⁷ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai, China; Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, the Naval Medical University and Ministry of Education, Shanghai, China.
⁸ National Center for Liver Cancer, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, the Naval Medical University and Ministry of Education, Shanghai, China. Electronic address: dlw@smmu.edu.cn.
⁹ National Center for Liver Cancer, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai, China; Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, the Naval Medical University and Ministry of Education, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, China. Electronic address: hywangk@vip.sina.com.

PMID: 36436593
DOI: 10.1053/j.gastro.2022.11.025

Abstract

Background & aims: In eukaryotes, the ubiquitin-proteasome system and the autophagy-lysosome pathway are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear.

Methods: We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis.

Results: PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies, which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts.

Conclusions: In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Keywords: Cholangiocarcinoma; Exosome; Lysosome; MVB; PTEN; TFEB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
Cholangiocarcinoma* / metabolism
Disease Models, Animal
Exosomes* / metabolism
Humans
Lysosomes / physiology
Mice
PTEN Phosphohydrolase* / metabolism
Proteasome Endopeptidase Complex
Retrospective Studies

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Proteasome Endopeptidase Complex
PTEN Phosphohydrolase
PTEN protein, human
TFEB protein, human
Pten protein, mouse
Tcfeb protein, mouse