Thematic Axis: Resistance and Therapy

Head of the axis : Erika Cosset

In cancer, tumor progression due to drug resistance limits the efficacy of most systemic therapies. Resistance to treatment can be driven by various mechanisms arising from epigenetic, genetic, transcriptional and translational factors, and modifications of the tumor microenvironment. Therefore, a better understanding of the molecular mechanisms underlying cancer treatment resistance is critical to identify and develop more effective therapeutic strategies. The vast majority of CRCL teams are interested in identifying cancer resistance mechanisms that lead to tumor progression and relapse. Our goals are: 1/ to identify compensatory activation pathways, 2/ to investigate drug inactivation and on-target resistance mechanisms, 3/ to study tumor cell plasticity and the role of the tumor microenvironment and 4/ to understand the mechanisms related to inhibition of cell death or enhanced DNA repair.

Antigen presentation, T-cells and cancer

Team leaders: Stéphane Depil & Jenny Valladeau-Guilemond
The aim of the team DEPIL/VALLADEAU is to develop new immunotherapies through the identification of new tumor antigens, pathways and molecules enhancing antigen presentation within the tumor, and T cell engineering to overcome resistances. In this context, a better understanding of the tumor heterogeneity is absolutely needed.

Cancer cell plasticity in melanoma

Team leaders: Julie Caramel & Stéphane Dalle
Team characterizes the mechanisms of cancer cell plasticity in melanoma and their crosstalk with the tumor microenvironment in promoting melanoma progression and resistance to both targeted and immunotherapies.

Cancer ecosystem dynamics, adaptation and modeling

Team leader: Pierre Saintigny
Team investigates how EMT-driven phenotypic plasticity and genetic evolution promote therapy persistent-residual disease and drug resistance. Using lung cancer and head-and-neck cancer as model systems, we combine translational and experimental biology, together with mathematical modelling and computational biology, to identify preclinical therapeutic rationales to improve response to treatment.

Cell States and Childhood Cancers

Team leaders: Marie Castets & Jean Yves Blay
Team uses innovative models of pediatric cancers to identify tumor vulnerabilities and evaluate new drug combinations, with the final aim of providing the preclinical proof-of-concept of their efficiency. As treatments can induce normal and cancer cell senescence, we aim to better apprehend the role of these senescent cells in tumor resistance and as potential target for therapy.

Endocrine resistance, methylation and breast cancer

Team leaders: Muriel Le Romancer & Olivier Trédan
The team Le Romancer/Trédan is interested in better understanding the signaling of steroid receptor and their modification by methylation in breast cancer to identify predictive biomarkers of response to therapies and new targets to avoid relapse.

Gastroenterology and technologies for health

Team leaders: Benjamin Gibert & Thomas Walter
The Gastroenterology and Technologies for Health team aims to better understand the biology of neuroendocrine tumours of the small intestine and, in particular, to identify new innovative targets and therapies.

Genetics, Epigenetics and Biology of Sarcomas

Team leader: Franck Tirode
Tirode team is interested in developing new strategies to block the function of some fusion genes found in specific sarcomas. We also aim at characterizing patients’ tumor circulating cells to capture treatment resistance mechanisms.

Glioblastoma metabolism and heterogeneity, in 3D organoids

Team learder: Erika Cosset
The team Cosset aim at understanding how GBM heterogeneity generates a “tumor ecosystem” that induces a stress-tolerant state and resistance in response to various tumor microenvironmental stresses.

KidsCaN – Kids & Cancer Neuroscience

Team leader: Céline Delloye-Bourgeois
Team works specifically on pediatric cancers, and aims to understand how certain signaling pathways, directly related to embryonic development, contribute to the response mechanisms and resistance of these cancers to anticancer agents.

Microenvironmental signalling in tumour dissemination

Team leader: Julien Ablain
Team approaches mechanisms of drug resistance through their molecular parallels with mechanisms of tumor dissemination in melanoma.

Molecular Regulation of Cancer Immunity

Team leader: Yenkel Grinberg-Bleyer
The team « Molecular Regulation of Cancer Immunity » explores the function of NF-kB transcription factors in the response and resistance to immunotherapies.

Onco-pharmacology

Team leaders: Lars Jordheim and Charles Dumontet
“Onco-pharmacology” team is interested in deciphering mechanisms of resistance to a variety of anticancer drugs including targeted therapies, monoclonal antibodies and chemotherapy, and works on various approaches for the treatment of resistant patients.

Ribosome, translation and cancer

Team leader: Jean-Jacques Diaz
The Diaz team aims to elucidate the role of ribosome, especially chemical modifications of ribosomal RNAs, in the synthesis of specific proteins that contribute to cell plasticity under therapeutic pressure, particularly in response to chemotherapy.

Targeting non-canonical protein functions in cancer

Team leaders: Toufic Renno
Team project aims at addressing the common challenge of resistance linked to kinase inhibitors. Indeed, the Renno/Coste team has identified a novel ERK/MyD88 protein-protein interaction as a therapeutic target. They have developed small molecule inhibitors that effectively eliminate cancer cells without triggering resistance. These inhibitors are now in pharmaceutical development, with plans for a Phase I clinical trial.