In response to chemotherapy, cells undergo apoptosis or senescence, a long term cell cycle exit where cancer cells remain viable but proliferation is definitely arrested. Initially characterized in primary cells, animalmodels and human biopsies have demonstrated that senescence limits tumor progression and is necessary forchemotherapy response. It is however unclear if chemotherapy-induced senescence (CIS) is always irreversibleand if some cells preserve their proliferative potential, for instance as a consequence of an intrinsic resistanceprogram. We initially described that the STAT3 pathway plays an important role in CIS resistance during theacute response. We showed that this oncogene prevents senescence signaling and activates DNA repair genes to allow drug resistance. This is due to STAT3 regulation by a neuronal kinase, cdk5, that phosphorylates the transcription factor on its C-terminal serine 727 residue. This observation was new and important, confirmed by several groups, since the main STAT3 activation site was believed to be Y705. Besides classical cytokine signaling, this has defined a new function and new target genes for STAT3 during the initial steps of CIS.
Our initial results were obtained during the early senescence response, assuming that no cells would maintain their proliferative potential. Using different senescence models, we then showed that colorectal and breast cells escape CIS and emerge as more agressive populations. Malignant cells that resist senescence are more transformed and invasive, they induce tumor formation in mice, resist anoikis and favor angiogenesis.
This phenotypic adaptation relies on Mcl-1, a new dependency acquired during emergence. Since senescentcells favor chemotherapy escape through the production of a specific secretome or SASP, we used quantitative proteomic and tumor samples to identify secreted proteins involved in this progression. We described and patented the first proteomic signatures of the successive stages of colorectal cancer and of triple negative breast cancers. We focused on the tumor secretome and identified specific markers of different stages that can be detected in the blood. With a first focus on OLFM4 and TSP1, we are now determining if these soluble proteins are involved in treatment failure and CIS escape.
Our research project is therefore focused on the identification of soluble and detectable markers of tumor progression and on the way tumor cells use this secretome to escape CIS. We will continue this project, and two connected research axis will be developped:
1. Using our proteomic approach, we will identify a senescence secretome and characterize its diagnosis and predictive values using a simple blood test. We will 1) determine if we can increase the predictive value ofmammograms and MRIs
2) determine if serum biomarkers predict the efficacy of neoadjuvant treatments in breast and rectal cancers.
2. We will study the role of this secretome during CIS failure and during the generation of more aggressive and invasive cells. We will 1) determine if these secreted proteins select a driving subpopulation that outcompete less fit clones, linking heterogeneity variation and its signaling to the efficiency of CIS escape and anoikis resistance 2) determine the role of STAT3 in the activation of this secretome and identify new STAT3 posttranslational modifications involved in the secretome transcriptional regulation and in sub-clone emergence.
O. Coqueret, PU
C. Guette, CR ICO
E. Lelièvre, PA
V. Verriele, PH ICO
I. Valo, PH ICO
P. Raro, PH ICO
M. A. Marouf, PhD student
M. le Duff, PhD student
R. Jatal, PhD student
J. Guillon, PhD student
C. Petit, PhD student
E. Lasserre, Master 2
B. Toutain, IE Univ
A. Boissard, TR ICO
L. Legrand, TR Univ
C. Henry, TR ICO
J. Renaud, TR
Coqueret O. Senescence: Adaptation to DNA repair targeting drugs? Cell Cycle. (2016)
Jonchère B, Vétillard A, Toutain B, Guette C and Coqueret O. Contribution to tumor escape and chemotherapy response: A choice between senescence and apoptosis in heterogeneous tumors. Bull Cancer. (2016)
Campone M, Valo I, Jézéquel P, Moreau M., Boissard A, Campion L, Loussouarn D, Coqueret O and Guette C. Prediction of recurrence and survival for triple-negative breast cancer by a protein signature in tissue samples. Mol Cell Proteomics. (2015)
Jonchère B, Vétillard A, Toutain B, Lam D, Bernard AC, Henry C, De Carné S, Gamelin E, Juin O, Guette C and Coqueret O. Irinotecan treatment and senescence failure promote the emergence of more transformed and invasive cells that depend on anti-apoptotic Mcl-1. Oncotarget. (2015)
Rideau A, Besson D, Boissard A, Coqueret O, Guette C. Two-step OFFGEL approach for effective peptide separation compatible with iTRAQ labeling. Proteomics. (2013)
Sellier H, Rébillard A, Guette C, Barré B, Coqueret O. How should we define STAT3 as an oncogene and as a potential target for therapy? JAKSTAT. (2013)
Jonchère B, Bélanger A, Guette C, Barré B, Coqueret O. STAT3 as a new autophagy regulator. JAKSTAT. (2013)
Weber A, Borghouts C, Delis N, Mack L, Brill B, Bernard AC, Coqueret O, Groner B. Inhibition of Stat3 by peptide aptamer rS3-PA enhances growth suppressive effects of irinotecan on colorectal cancer cells. Horm Mol Biol Clin Investig. (2012) .
Basseville A, Preisser L, de Carné Trécesson S, Boisdron-Celle M, Gamelin E, Coqueret O, Morel A. Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells. Mol Cancer. (2011)
Besson D, Pavageau AH, Valo I., Bourreau A, Bélanger A., Eymerit C., Moulière Chassevent A., Boisdron-Celle M., Morel A., Solassol J.,Campone M., Gamelin E., Barré B., Coqueret O. and C. Guette. A QuantitativeProteomic Approach Identifies Stratification Signatures of the Different Stages of Colorectal Cancer and Establishes OLFM4 as a New Non-Invasive Tumor Marker. Mol Cell Proteomics. (2011)
de Carne Trecesson S, Guillemin Y, Belanger A, Bernard AC, Preisser L, Ravon E, Gamelin E, Juin P, BarreB, Coqueret O. Escape from p21-mediated oncogene-induced senescence leads to cell dedifferenciation and dependency on anti-apoptotic Bcl-xL and Mcl1 proteins. J Biol Chem. (2011)
Courapied S, H. Sellier, S. De Carne Trecesson, A. Vigneron, A.C. Bernard, E. Gamelin, B. Barré and O. Coqueret. The cdk5 kinase regulates the STAT3 Transcription factor to prevent DNA damage upon topoisomerase I inhibition. J. Biol Chem . (2010)
Ligue Contre le Cancer
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