Role of tumor heterogeneity in treatment resistance
The tumor cellular heterogeneity of both stromal and tumor cells has to be taken into account in the treatment of cancer patients, since it is involved, at least in part in the treatment resistance mechanisms and therapeutic relapses. By characterizing tumor and stromal heterogeneity, we uncovered differences in response to treatments currently used in clinics.
- Metabolic heterogeneity of tumor cells in ovarian cancers (HGSOC) is associated with a difference in sensitivity to chemotherapy
In HGSOC, we found two tumor cell populations "low-OXPHOS" and "high-OXPHOS", revealing inter-patient tumor metabolic heterogeneity (Gentric et al, Cell Metabolism, 2019). We evaluated the impact of tumor metabolism on the response to conventional chemotherapy. By the study of preclinical models, we demonstrated that the high-OXPHOS signature is associated with an increased chemosensitivity to conventional treatments (platinum salts and taxanes), independent of the BRCAness. In patients with HGSOC, the high expression of ETC proteins in tumors is associated with better survival. In collaboration with Dr. Raphael Rodriguez team at the Institut Curie, we have shown that the tumor cell sensitivity can be explained, in part by ferroptosis; an iron-dependent programmed cell death. Thus, “high-OXPHOS” tumors, subjected to chronic oxidative stress, are characterized by an increased sensitivity to chemotherapy based on the accumulation of ROS, alteration of mitochondria and induction of ferroptosis (Gentric et al, Cell Metabolism, 2019).
Although high-OXPHOS status is associated with better response to treatment, the vast majority of ovarian cancer patients relapse after treatment, underscoring the need to identify mechanisms of resistance to treatment. We therefore wish to investigate intra-tumoral metabolic heterogeneity as well as the metabolic plasticity induced after chemotherapy. We wish to investigate the molecular mechanisms of resistance to treatment (conventional chemotherapy, immunotherapies).
- Development of a 3D co-culture model to study the cellular interactions involved in resistance to treatments: Tumor-On-Chip
Our work shows the importance of considering the tumor as a whole in order to understand how the responses to the different treatments used in the clinic are mediated. In the laboratory, we want to develop new technologies to get closer to the physiopathology and physiognomy of tumors. 3D culture techniques allowing the incorporation of different cell types are booming and very promising. Indeed, they permit to reconstruct the complexity of the tumors from a structural, biochemical and biophysical point of view, and to question the relationships existing between the different cell populations in basal conditions or in consequence of a treatment. In collaboration with Dr Stéphanie Descroix's team, our research team is developing a 3D cell co-culture model: the Tumor-on -Chip (ToC). This approach, based on a microfluidic device, allows to reconstitute ex-vivo the complexity of the tumor ecosystem. In combination with a video-microscopy system, we can visualize cell dynamics in real time. We are thus able to study, in an integrated manner, the cellular mechanisms involved in responses to treatments and to characterize all the spatio-temporal relationships existing between stromal, immune and tumor cells.
Related team publications:
- Parrini MC. Models for Immuno-oncology research. Tumour-on-chip breakthrough. Cancer Cell. 2020, 10;38(2):145-147. https://doi.org/10.1016/j.ccell.2020.07.010.
- 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.
- Nguyen M, De Ninno A, Mencattini A, Mermet-Meillon F, Fornabaio G, Evans SS, Cossutta M, Khira Y, Han W, Sirven P, Pelon F, Di Giuseppe D, Bertani FR, Gerardino A, Yamada A, Descroix S, Soumelis V, Mechta-Grigoriou F, Zalcman G, Camonis J, Martinelli E, Businaro L, Parrini MC. Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments. Cell Report 2018, 26;25(13):3884-3893.e3. https://doi.org/10.1016/j.celrep.2018.12.015.