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, DR ICO
E. Lelièvre, MCF
D. Pouliquen, CR Inserm
A. Patsouris, PH ICO
V. Verriele, PH ICO
I. Valo, PH ICO
P. Raro, PH ICO
B. Toutain, IE Univ
A. Boissard, TR ICO
C. Henry, TR ICO
C. Petit, Doctorant
A. Marouf, Doctorant
R. Jatal, Doctorant
C. Tirand, Master 2
Guillon J, Petit C, Toutain B, Guette C, Lelièvre E and O. Coqueret. Chemotherapy-Induced Senescence, An Adaptive Mechanism Driving Resistance and Tumor Heterogeneity. Cell Cycle (2019).
Valo I, Raro P, Boissard A, Maarouf A, Jézéquel P, Verriele V, Campone M, Coqueret O, Guette C. OLFM4 expression in ductal carcinoma in situ and in invasive breast cancer cohorts by a SWATH-based proteomic approach. Proteomics (2019).
Petit C, Guillon J, Toutain B, Boissard A, Patsouris A, Lelièvre E, Guette C, Coqueret O. Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response. Proteomics. (2019)
Guillon J, Petit C, Moreau M, Toutain B, Henry C, Roché H, Bonichon-Lamichhane N, Salmon JP, Lemonnier J, Campone M, Verrièle V, Lelièvre E, Guette C, Coqueret O. Regulation of senescence escape by TSP1 and CD47 following chemotherapy treatment. Cell Death Dis. (2019)
Jézéquel P, Guette C, Lasla H, Gouraud W, Boissard A, Guérin-Charbonnel C, Campone M. iTRAQ-Based Quantitative Proteomic Analysis Strengthens Transcriptomic Subtyping of Triple-Negative Breast Cancer Tumors. Proteomics. (2019)
Nader JS, Abadie J, Deshayes S, Boissard A, Blandin S, Blanquart C, Boisgerault N, Coqueret O, Guette C, Grégoire M, Pouliquen DL. Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma. Oncotarget. (2018)
Le Duff M, Gouju J, Jonchère B, Guillon J, Toutain B, Boissard A, Henry C, Guette C, Lelièvre E, Coqueret O. Regulation of senescence escape by the cdk4-EZH2-AP2M1 pathway in response to chemotherapy. Cell Death Dis. (2018)
Carné Trécesson S, Souazé F, Basseville A, Bernard AC, Pécot J, Lopez J, Bessou M, Sarosiek KA, Letai A, Barillé-Nion S, Valo I, Coqueret O, Guette C, Campone M, Gautier F, Juin PP. BCL-X(L) directly modulates RAS signalling to favour cancer cell stemness. Nat Commun. (2017)
Coqueret O. Senescence: Adaptation to DNA repair targeting drugs? Cell Cycle. (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)
Guette C, Valo I, Vétillard A, Coqueret O. Olfactomedin-4 is a candidate biomarker of solid gastric, colorectal, pancreatic, head and neck, and prostate cancers. Proteomics Clin Appl. (2015)
Vétillard A, Jonchère B, Moreau M, Toutain B, Henry C, Fontanel S, Bernard AC, Campone M, Guette C, Coqueret O. Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis. Oncotarget. (2015)
Ligue Contre le Cancer
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