Work

Deciphering the Role of ADAMTS6 in the Epithelial–Mesenchymal Transition of Lung Adenocarcinoma Cells

Year: 2025

Type: article

Abstract: A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) is an extracellular protease that promotes the invasion of lung adenocarcinoma (LUAD) cells. Herein, we investigate its role in epithelial-mesenchymal transition (EMT), a process that drives metastasis and drug resistance in LUAD. Re-analysis of microarray and RNA sequencing data from LUAD cells reveals that during EMT, TGF-β1 increases ADAMTS6 expression, presumably through the SMAD pathway, as SMAD2 loss completely blocks this effect. Moreover, it was shown that ADAMTS6 occupies hub positions within TGF-β1-associated gene networks. Using additional datasets, we found that ADAMTS6 expression increases under other EMT-inducing conditions, including IL-1β induction and acquired gefitinib resistance, but decreases upon knockdown of Twist1, a master regulator of EMT. This supports the involvement of ADAMTS6 in EMT within a broader context. Our knockout experiments in A549 cells showed that ADAMTS6 expression enhanced cell migration, invasion, colony formation, doxorubicin resistance, and expression of the mesenchymal markers N-cadherin, vimentin, and Twist1, but attenuated cell adhesion to the extracellular matrix and expression of the epithelial marker E-cadherin. Re-analysis of transcriptomic data from patient tumors demonstrates that high ADAMTS6 expression correlates with the expression of EMT markers, further supporting the ADAMTS6–EMT link. Moreover, high ADAMTS6 expression is associated with a worse survival prognosis. Overall, ADAMTS6 promotes EMT in LUAD cells and may be considered a marker of this process, as well as a potential therapeutic target for its inhibition.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms262411850

Authors: Kirill V. Odarenko, Anastasiya M. Matveeva, Grigory A. Stepanov, Marina A. Zenkova, Andrey V. Markov

Institutions: Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences

Language: English

Topic: Cancer Cells and Metastasis

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499