AXL Mediates Esophageal Adenocarcinoma Cell Invasion Through Regulation of Extracellular Acidification and Lysosome Trafficking

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2018 Sep 7

PMID 30189359

Citations 20

Authors

Selma Maacha

Jun Hong

Ariana von Lersner

Andries Zijlstra

Abbes Belkhiri

Affiliations

Soon will be listed here.

Abstract

Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.

Citing Articles

AXL signaling in cancer: from molecular insights to targeted therapies.

Yadav M, Sharma A, Patne K, Tabasum S, Suryavanshi J, Rawat L Signal Transduct Target Ther. 2025; 10(1):37.

PMID: 39924521 PMC: 11808115. DOI: 10.1038/s41392-024-02121-7.

RNASE4 promotes malignant progression and chemoresistance in hypoxic glioblastoma via activation of AXL/AKT and NF-κB/cIAPs signaling pathways.

Lee H, Chuang H, Lin K, Yeh C, Wang Y, Chi H Am J Cancer Res. 2024; 14(9):4320-4336.

PMID: 39417186 PMC: 11477813. DOI: 10.62347/UDBJ5986.

AXL as immune regulator and therapeutic target in Acute Myeloid Leukemia: from current progress to novel strategies.

Vandewalle N, De Beule N, De Becker A, de Bruyne E, Menu E, Vanderkerken K Exp Hematol Oncol. 2024; 13(1):99.

PMID: 39367387 PMC: 11453060. DOI: 10.1186/s40164-024-00566-8.

Reflux conditions induce E-cadherin cleavage and EMT via APE1 redox function in oesophageal adenocarcinoma.

Lu H, Cao L, Ballout F, Belkhiri A, Peng D, Chen L Gut. 2023; 73(1):47-62.

PMID: 37734913 PMC: 10872865. DOI: 10.1136/gutjnl-2023-329455.

Altered expression of AXL receptor tyrosine kinase in gastrointestinal cancers: a promising therapeutic target.

Pidkovka N, Belkhiri A Front Oncol. 2023; 13:1079041.

PMID: 37469409 PMC: 10353021. DOI: 10.3389/fonc.2023.1079041.

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