Understanding mesothelioma chemoresistance and implication of ADAM in this process

Mesothelioma is an aggressive cancer that affects mesothelial surfaces. The most recognized risk factor for mesothelioma is asbestos exposure since the fibres can reach the pleura and are not cleared. The cancerization might arise 30 to 40 years after exposure. The gold standard treatment is a combination of cisplatin and pemetrexed. Unfortunately, the available therapies have a limited impact and cancer cells quickly develop resistance to treatment.

Adamalysins constitute a family of zinc dependant proteases. Among them, ADAM (a disintegrin and metalloprotease) display a conserved structure made of various domains playing roles in cell to cell interactions, cell to extracellular matrix interactions as well as the shedding of some membrane proteins.
Numerous ADAM are implicated in processes leading to cancer development such as inflammation, invasion, angiogenesis and resistance to chemotherapy. ADAM8 has been described to be implicated in cisplatin resistance in NSCLC and bladder cancers.

This project aims at unveiling the mechanisms of treatment resistance induced by ADAM8 and other proteases in mesothelioma. The final goal will be the development of therapeutic strategies based on the inhibition of ADAM proteases.

In human mesothelioma samples, ADAM8 mRNA are overexpressed as compared to normal pleura samples. Therefore, we hypothesized that ADAM8 was implicated in cancer development and we started to investigate it in vitro.
We transfected AB12 murine mesothelioma cells with shRNA targeting ADAM8. These ADAM8-ShRNA cells treated with cisplatin displayed a decreased survival rate as compared to control-ShRNA treated cells. This indicates that ADAM8 might be implicated in cisplatin resistance.
Concurrently, we have generated 2 different mesothelioma cell lines resistant to cisplatin. The first is derived from AB12 cell line and the second derives from a cell line obtained by a primary cancerization mice model (6627). Briefly, the cells have been treated with increasing doses of cisplatin from 0,25 µM to 2 µM, a dose that would kill parental cell lines. The resistance of the treated cells was assessed by a cell proliferation array in presence of cisplatin and we confirm that these cisplatin-treated cell lines display an increased resistance to the drug. In the very next future, we will perform a RNA sequencing experiment in order to compare the cisplatin-resistant cell lines to the matching parental cells in order to determine which pathways are modified and would explain how the cells resist.

In conclusion, our results show that ADAM8 might be implicated in cisplatin resistance in mesothelioma. In our future researches, we will aim at discovering the molecular mechanisms of resistance to cisplatin. We hypothesize that our results will shed light on pathways differentially expressed between the parental and the resistant cell lines. By understanding the modified pathways, we hope to be able to prevent chemotherapy-resistant cells to emerge.