• E-mail :[email]
  • Phone : +33 1 56 24 66 53
  • Location : Paris, France
Last update 2012-11-01 07:49:05.15

Fatima MECHTA-GRIGORIOU PhD, DR1

Course and current status

After a classic university course, I have been recruited at the Pasteur Institute, where I have worked on the role of the AP-1 family of transcription factors (Jun genes) in oncogenesis. After being recruited as research Director in Inserm, I have created my own lab called "Stress and Cancer" at Institut Curie, in 2006. Our activity is mainly devoted to the role of oxidative stress in tumour development and response to treatment.

Academic position

  • 1994-2000: Researcher (CR2) - Institut Pasteur
  •  2000-2005: Researcher (CR1) - Institut Pasteur
  •  2005: Laureate of an Inserm Avenir contract
  •  2005: Group leader of the “Stress and Cancer” laboratory - Institut Curie, Paris
  •  2006: Research Director (DR2) – Inserm
  • 2011: Research Director (DR1) - Inserm

Participation to scientific committees

  • Member of the National commission CSS2 Inserm (2012- Now)
  • Member of the National commission n°24 CNRS (2009-2012)
  • Member of the scientific commission of the research department of Institut Curie (2011-Now)
  • Member of the National commissions ARC (n°4: 2012-Now)
  • Member of the National commissions ARC (n°2: 2005-2009)
  • Member of evaluation committees AERES (2009-Now)
  • Member of the French network of Angiogenesis (2006-Now)
  • Member of the editorial committee “Frontiers in Pharmacotherapy of Neoplastic Diseases”

Awards

  • 2005: Gustave Roussy Prize – French academy of Science
  • 2006: Olga Sain Prize - Ligue Nationale Contre le Cancer
  • 2006: Simone & Cino del Duca Prize - French academy of Science
  • 2010-2011: Prizes of Scientific Excellence

Scientific summary

My group investigates the pathophysiological consequences of oxidative stress, including its impact on tumour development. We have previously shown that persistent oxidative stress promotes aging by modulating insulin signalling (Laurent, Cell Metabolism, 2008). Moreover, while oxidative stress increases tumour development by deeply affecting components of the tumour micro-environment, such as blood vessels (Gerald, Cell, 2004) and fibroblasts (Toullec, EMBO Mol. Med., 2010), it can also improve response to treatments (Mateescu, Nature Medicine, 2011). We are now interested by studying in deep the complex interplay between oxidative stress and immune system. We plan to investigate the potential effect -either positive or negative- of chronic oxidative stress and related-metabolism on immunotherapy.

Specifically, in the past, we have shown that abnormal accumulation of reactive oxygen species (ROS) stabilizes the hypoxia-inducible factor (HIF)-1a transcription factor, under normoxic conditions. Accumulation of HIF-1a enhances both the secretion of the CXCL12 chemokine and the expression of its receptor, CXCR4. This promotes angiogenesis (Gerald, Cell, 2004; Laurent, Cell Metabolism, 2008) as well as conversion of fibroblasts into highly migrating myofibroblasts, further stimulating tumour cell spreading (Toullec, EMBO Mol. Med., 2010). In agreement with our results on mouse models, we have observed that the ERBB2-amplified breast cancer subtype (also referred to as HER2) exhibited the highest expression levels of CXCL12/CXCR4, the highest correlated proportion of myofibroblasts and rate of axillary lymph node metastasis, when compared to aggressive basal-like breast cancers (BLC) or to good prognosis luminal-A (Lum-A) breast carcinomas. Interestingly, the transcriptomic signature, which differentiates, the most efficiently, the two aggressive subtypes of breast cancers (BLC and HER2) is an oxidative stress signature (Toullec, EMBO Mol. Med., 2010).

Intriguingly, although oxidative stress promotes tumour development and metastasis, it can also improve response of ovarian cancer patients to chemotherapeutic agents (Mateescu, Nature Medicine, 2011). We have indeed identified two different sets of ovarian cancer patients, characterized by a miR200a-dependent dual signature involved either in “Fibrosis” or in “Oxidative Stress”. These signatures have a predictive value on patient survival, with a better survival rate for the “Stress” patients, compared to the “Fibrosis” ones. Indeed, while miR-200a overexpression and its subsequent oxidative stress severely increase tumorigenesis, they are also able to improve the pro-apoptotic effect of ROS-producing chemotherapeutic agents, further increasing patient survival (Mateescu, Nature Medicine, 2011).

In conclusion, chronic oxidative stress is both deleterious and beneficial for survival of patients suffering from cancer: it severely affects tumour micro-environment and promotes tumor development and aggressiveness but, in the mean time, it can also improve response to treatment. We have referred this effect to as the paradoxical effect of ROS.

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