SIGNALPHAGY

Research themes

Since 2004, my research activity has been devoted to understand the tumor suppressive function of autophagy particularly in non-small cell lung cancer (NSCLC), which is the leading cause of cancer death worldwide. To succeed in this effort, I conduct a multidisciplinary program integrating basic, clinical, molecular, and genetics approaches. I recruited a postdoc (A Chargui now MCU, University of Tunis), two PhD students (E Corcelle now senior researcher Denmark, and A Belaid, post-doctoral fellow at Harvard Medical School USA) and five technicians/engineers (M Nebout, Djerbi N, P Ndiaye, N Durand, B Romeo).

A. Homeostasis and tumor suppression – Concept of Signalphagy

Specifically, our works describe an important discovery concerning the control of the RHOA pathway by autophagy.

• We indeed provide the first evidence that i) the autophagy pathway specifically degrades the membrane-associated and active pool of RHOA, ii) a failure in autophagy activity (irrespective of the studied defects: formation, sequestration, or degradation, by ShRNA or knockout strategies) deregulates all RHOA downstream responses, driving cytokinesis failure, and aneuploidy, one hallmark of aggressive lung cancer (Nice tumor biobank) (Belaid A. et al. Cancer Res 2013).
• In keeping with this scenario, we demonstrate that autophagy is absolutely necessary for maintaining the appropriate amount of RHOA at the lamellipodia to allow tumor cell motility (Belaid A. et al. Autophagy 2014).
• Mechanistically, this selective autophagy of active RHOA stems on the autophagy adapter SQSTM1/p62. We therefore propose the term “signalphagy” to indicate a dedicated type of macroautophagy that degrades and thereby maintains the appropriate level of active signaling proteins (kinases, substrates and downstream transcription factors) to achieve tumor suppression (Belaid A. et al. Autophagy 2013).

B. Inhibition by pollutants / environmental carcinogens

Supported by ADEME, the Health and Environment Plan (ARS and DREAL), the PACA region and ANR, we provided the first evidence that:

• Autophagy is inhibited by different classes of xenobiotics (pesticides, heavy metals, and nanoparticles); explaining the observed toxic, inflammatory and carcinogenic effects (Corcelle E et al. Cancer Res 2006 ; Autophagy 2007 ; Chargui A et al. Toxicol Sci. 2011 ; Eidi H et al. Int J Pharm. 2012).
• Exposure to the human carcinogen Cadmium at extremely low doses, close to an environmental exposure, is able to inhibit autophagy in vivo (Chargui A et al. Toxicol Sci 2011, Curr Chem Biol 2011).
• In particular, only the constitutive autophagy is suppressed by cadmium, leading to aggregation of polyubiquitinated proteins, and the subsequent exacerbated inflammation of bronchial cells (Belaid A Chargui A et al. 2015 revision).

Composition de l'équipe

Baharia Mograbi, CR1
Nelly Durand, AI
Barnabé Roméo, AI