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Characterizing diversity of tumor cells in cancer

The characterization of tumor cell diversity (transcriptomics, proteomics, metabolomics) in cancer represents a major challenge for better understanding tumor development, cell interactions and mechanisms of resistance to treatments. Historically, the "Stress and Cancer" laboratory has been interested in the link between oxidative stress, cell aging and tumor development. Indeed, cancer being one of the most frequent pathologies related to aging, we were interested in the impact of a persistent oxidative stress on tumor development. We have thus shown that:

  • Oxidative stress stimulates tumor growth and metastatic dissemination, by profoundly modifying the tumor microenvironment through the action of the CXCL12 chemokine and the pro-angiogenic factor HIF in invasive HER2-positive breast cancers (Gerald et al, Cell, 2004; Toullec et al, EMBO Molecular Medicine, 2010; Dahirel et al, Cell cycle, 2013; Costa et al, Seminars Cancer Biology, 2014).
  • Oxidative stress enhances chemotherapy response in patients with high-grade serous ovarian carcinoma (HGSOC). HGSOC patients are conventionally treated with taxanes and platinum salts, known to generate reactive oxygen species (ROS) and DNA damages. The positive impact of oxidative stress in the chemotherapy response are link to the miR-200 family of microRNAs. We highlighted two groups of HGSOC patients: the first one characterized by an oxidative stress signature and a better response to chemotherapy, and the “Fibrosis/Mesenchymal” subgroup with a worse prognosis (Mateescu et al, Nature Medicine, 2011; Batista et al, International Journal of Biochemistry and Cell Biology, 2013; Batista et al, Nature Communications, 2016).

 

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The study of oxidative stress in patients with high-grade serous ovarian cancer (HGSOC) revealed two groups of patients: "oxidative stress" and "fibrous". Patients with a transcriptomic profile revealing an enrichment of genes involved in the response to oxidative stress have a better response to chemotherapy and thus a better prognosis (Mateescu et al, Natude Medicine, 2011).

 

  1. HGSOC are among the most aggressive gynecologic diseases. Linked with the response to oxidative stress, we have performed two studies that demonstrate the tumor cell heterogeneity in these cancers, following two topics: cell metabolism and the signaling pathway induced by MAP3K8.

     

  2. The study of cell metabolism in HGSOCs:

 

Metabolic reprogramming is defined as one of the “Hallmark” of cancers (Gentric et al, Antioxidants and Redox Signaling, 2017, Gentric et Mechta-Grigoriou, Cancers, 2021). By combining proteomic, metabolomic and functional approaches (Seahorse, 13C-fluxomics, siRNA, xenografts), we identified a metabolic signature that distinguishes 2 HGSOC subgroups, low-OXPHOS and high-OXPHOS. Low-OXPHOS tumors are dependent of aerobic glycolysis or "Warburg Effect", while high-OXPHOS tumors use oxidative phosphorylation (OXPHOS). These results highlight, for the first time, the inter-tumor metabolic heterogeneity in ovarian cancers (Gentric et al, Cell Metabolism, 2019).

 

Interestingly, although no specific genomic alterations have been identified in high-OXPHOS tumors, this status appears to be associated with a deficiency in DNA repair mechanisms, homologous recombination type. As this deficiency in homologous recombination may be associated with chronic oxidative stress, we have demonstrated that “high-OXPHOS” HGSOC are characterized by a chronic oxidative stress, which promotes the accumulation and aggregation of PML (ProMyelocytic Leukemia) and activates the co-activator of mitochondrial biogenesis PGC1⍺ (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). The PML-PCG1⍺ axis promotes the expression of respiratory chain complex genes leading to an increased mitochondrial respiration in these cells (Gentric et al, Cell Metabolism, 2019).

 

 

Perspectives de recherche :

Nous souhaitons investiguer l’hétérogénéité métabolique intra-tumorale afin de faire le lien entre fonction moléculaire, propriété métabolique et localisation spatiale au sein de la tumeur. Nous souhaitons également déterminer les mécanismes à l’origine de la plasticité métabolique et les trajectoires des différents clones cellulaires. Enfin, nous caractériserons les interactions entre les différents clones cellulaires avec leur microenvironnement tumoral.

 

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“High-OXPHOS” high-grade serous ovarian cancers are subjected to chronic oxidative stress by the presence of reactive oxygen species (ROS) which causes the activation of the PML-PCG1⍺ pathway leading to an increased expression of ETC genes and an increased mitochondrial respiration. Therefore, “high-OXPHOS” cells metabolism rely on the oxidative phosphorylation pathway (Gentric et al. Cell metabolism, 2019).

 

 

1. Research perspectives:

We wish to investigate intra-tumoral metabolic heterogeneity in order to establish the link between molecular function, metabolic property and spatial location within the tumor. We also want to determine the mechanisms behind metabolic plasticity and the trajectories of different cell clones. Finally, we will characterize the interactions between the different cell clones with their tumor microenvironment.

 

2. The study of the MAP3K8-ERK signaling pathway in HGSOCs:

In line with our studies concerning the response to oxidative stress in ovarian cancers, we have demonstrated, through proteomic studies on HGSOC tumor patients, the accumulation of the kinase protein MAP3K8, marker of poor prognosis, in 50% of HGSOC tumors (Gruosso et al, Nature Communications, 2015). MAP3K8 accumulation leads to a constitutive activation of the MEK/ERK signaling pathway in the absence of KRAS or BRAF mutation. There is therefore inter-tumor heterogeneity of the MAP3K8/MEK signaling pathway in HGSOC patients. We have shown that MAP3K8 exerts pro-tumorigenic functions mediated by MEK/ERK and that this protein kinase has predictive value for the efficacy of MEK inhibitors. Our work underlines the potential interest of the use of anti-MEKs in high-grade ovarian cancers for patients who present a strong MAP3K8 expression, whereas they are currently only tested in ovarian cancers of low-grade mutated for KRAS or BRAF oncogenes (Gruosso et al, Nature Communications, 2015; Patent application number: EP14306434, 2015).

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Research perspectives:

Most oncogenic signaling pathways including MEK/ERK lead to translational reprogramming of the genome by activating eIF4F, a translation initiation complex. We have shown that constitutive activation of MEK/ERK, due to the accumulation of MAP3K8 in HGSOCs, controls the formation and activity of the eIF4F complex, thereby inducing translation of a set of specific mRNAs. We now wish to determine the causes and consequences of translational reprogramming induced by MAP3K8/MEK in HGSOCs on tumor development and response to treatments.

 

Related team publications:

  • Gentric G., Mechta-Grigoriou F. Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective. Cancers 2021 Jan 22;13(3):399. doi: 10.3390/cancers13030399.
  • Gentric, G.; Kieffer, Y.; Mieulet, V.; Goundiam, O.; Bonneau, C.; Nemati, F.; Hurbain, I.; Raposo, G.; Popova, T.; Stern, M.-H.; Lallemand-Breitenbach, V.; Müller, S.; Cañeque, T.; Rodriguez, R.; Vincent-Salomon, A.; de Thé, H.; Rossignol, R.; Mechta-Grigoriou, F. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metabolism 2019, 29 (1), 156-173.e10. https://doi.org/10.1016/j.cmet.2018.09.002.
  • Gentric, G.; Mieulet, V.; Mechta-Grigoriou, F. Heterogeneity in Cancer Metabolism: New Concepts in an Old Field. Antioxidants and Redox Signaling 2017, 26 (9), 462–485. https://doi.org/10.1089/ars.2016.6750.
  • Batista, L.; Bourachot, B.; Mateescu, B.; Reyal, F.; Mechta-Grigoriou, F. Regulation of MiR-200c/141 Expression by Intergenic DNA-Looping and Transcriptional Read-Through. Nature Communications 2016, 7. https://doi.org/10.1038/ncomms9959.
  • Gruosso, T.; Garnier, C.; Abelanet, S.; Kieffer, Y.; Lemesre, V.; Bellanger, D.; Bieche, I.; Marangoni, E.; Sastre-Garau, X.; Mieulet, V.; Mechta-Grigoriou, F. MAP3K8/TPL-2/COT Is a Potential Predictive Marker for MEK Inhibitor Treatment in High-Grade Serous Ovarian Carcinomas. Nature Communications 2015, 6. https://doi.org/10.1038/ncomms9583.
  • Costa, A.; Scholer-Dahirel, A.; Mechta-Grigoriou, F. The Role of Reactive Oxygen Species and Metabolism on Cancer Cells and Their Microenvironment. . Seminars in Cancer Biology 2014, 25, 23–32. https://doi.org/10.1016/j.semcancer.2013.12.007.
  • Batista, L.; Gruosso, T.; Mechta-Grigoriou, F. Ovarian Cancer Emerging Subtypes: Role of Oxidative Stress and Fibrosis in Tumour Development and Response to Treatment International Journal of Biochemistry & Cell Biology 2013, 45 (6), 1092–1098. https://doi.org/10.1016/j.biocel.2013.03.001.
  • Scholer-Dahirel, A.; Costa, A.; Mechta-Grigoriou, F. Control of Cancer-Associated Fibroblast Function by Oxidative Stress: A New Piece in the Puzzle. Cell Cycle 2013, 12 (14), 2169. https://doi.org/10.4161/cc.25547.
  • Mateescu, B.; Batista, L.; Cardon, M.; Gruosso, T.; de Feraudy, Y.; Mariani, O.; Nicolas, A.; Meyniel, J.-P.; Cottu, P.; Sastre-Garau, X.; Mechta-Grigoriou, F. MiR-141 and MiR-200a Act on Ovarian Tumorigenesis by Controlling Oxidative Stress Response. Nature Medicine 2011, 17 (12), 1627–1635. https://doi.org/10.1038/nm.2512.
  • Toullec, A.; Gerald, D.; Despouy, G.; Bourachot, B.; Cardon, M.; Lefort, S.; Richardson, M.; Rigaill, G.; Parrini, M.-C.; Lucchesi, C.; Bellanger, D.; Stern, M.-H.; Dubois, T.; Sastre-Garau, X.; Delattre, O.; Vincent-Salomon, A.; Mechta-Grigoriou, F. Oxidative Stress Promotes Myofibroblast Differentiation and Tumour Spreading. EMBO Molecular Medicine 2010, 2 (6), 211–230. https://doi.org/10.1002/emmm.201000073.