Lecture Dr. Carine Michiels | Hypoxia induces cancer resistance to chemo- and radio-therapies

Hypoxia induces cancer resistance to chemo- and radio-therapies

Important contributions of the Michiels’ team are the better understanding the cell responses to hypoxia, notably the ones involving gene expression regulation and the study of the effects of hypoxia on cancer cell survival. These responses allow cancer cells to survive the hypoxic conditions developing in the tumor microenvironment but also to become resistant to chemotherapy. For example, the team has shown that hypoxia protects cancer cells from the apoptosis induced by etoposide or paclitaxel. Invalidation studies using siRNA evidenced that the transcription factor HIF-1 is a major regulator of this resistance. In addition, hypoxia also inhibits p53 activation, thus preventing apoptosis to be initiated. Finally, the group has also shown that etoposide also induces autophagy that participates to cell death under normoxia but not under hypoxia, probably through a different regulation of BNIP3 expression and/or function and via JNK activation. Since then, hypoxia is now recognized as a major factor involved in cancer chemoresistance.

Through a whole genome transcriptomic approach, Michiels’ team discovered TMEM45A as a new gene, induced by hypoxia, responsible for cancer cell resistance. TMEM45A is a transmembrane protein whose expression is correlated to a low cancer patient overall survival. Using head and neck squamous cell carcinoma and renal cell carcinoma biopsies, it was shown that TMEM45A is upregulated in the tumors when compared to the corresponding adjacent healthy tissues. TMEM45A inactivation decreased cell proliferation and modulated cell responses to several chemotherapeutic drugs. Through RNA-sequencing analysis, several dysregulated pathways were identified that indicated that the impact on drug sensitivity may be associated to the inhibition of DNA damage repair and to UPR pathway activation. This study highlighted the role of TMEM45A in modulating cancer cell responses to treatment.

In addition to inducing chemoresistance, hypoxia also modulates cell responses to radiotherapy and initiates a pro-inflammatory feedback loop maintaining endothelial cell and macrophage activation.

In conclusion, hypoxia via these different processes is a major cancer hallmark involved in tumor growth and aggressiveness.