Implication de la protéine TMEM45A dans la chimiorésistance

PhD thesis defended by Kathleen SCHMIT (Prof. Carine MICHIELS) - 27/03/2019
Promoter

Prof. Carine MICHIELS, UNamur, Laboratory of Cellular and Molecular Biology (URBC), Tumor Hypoxia (TumHyp) group

Jury

Poumay Yves (UNamur), président; Michiels Carine (UNamur), secrétaire; Noel Agnès (ULiège); Graux Carlos (CHU UCL UNamur); Gillet Jean-Pierre (UNamur)

Summary

Successful remission can be achieved with chemotherapy in most cases of cancer but refractory diseases and relapses remain a major obstacle. Resistance to treatment can appear by intrinsic adaptation of cancer cells themselves but also by features of the tumor microenvironment, and more specifically hypoxia (1% O2). In this condition, the transcription factor HIF-1 is stabilized leading to the transcription of several target genes such as TMEM45A. The aim of the project is to pursue the study of the contribution of this protein in modulating the responses to treatment and of the mechanisms by which it acts.

The role of TMEM45A in the resistance to chemotherapy has been studied in two models: head and neck squamous cell carcinoma (SQD9 cells) and renal cell carcinoma (RCC4 plus pVHL). TMEM45A influences the drug sensitivity of cancer cells depending on the cancer type through a modulation of cisplatin-activation of UPR pathway leading to the resistance of RCC4 plus pVHL cells, whereas it increased SQD9 cell sensitivity to cisplatin through the deregulation of cell responses to cisplatin-induced DNA damage. Furthermore, this protein seems to be involved in tumor growth in vivo. Altogether our data emphasize the involvement of TMEM45A in tumor aggressiveness and suggest that TMEM45A might be used as a marker of patient responses to treatment.