Rho-mediated cellular plasticity during lung cancer progression and resistance to therapy

Olivier Calvayrac

Our main objective is to decipher the molecular mechanisms and signaling pathways underlying lung cancer progression and resistance to anticancer therapies. Our work is particularly focused on the Rho GTPases family that controls a wide variety of signal transduction pathways in response to cellular stress. We have shown that the RAS-related small GTPase RhoB plays a pivotal role in several oncogenic processes such as invasion (1-3), cell cycle progression (4) or resistance to targeted therapies (5-7). Although genetic alterations such as mutations, amplifications/deletions or translocations have long been considered the main determinant of tumor progression and response/resistance to therapies, phenotypic plasticity of cancer cells mediated by profound transcriptional reprogramming has recently emerged as a key non-genetic event underlying oncogenesis and therapeutic failure. These observations have been facilitated by the development of new technologies such as single-cell omics that have deepen our understanding of the tumors. In this context, our group investigate how RhoB but also other Rho GTPases and Rho-associated pathways contribute to lung cancer cell plasticity in different oncogenic situations in order to propose alternative therapeutic strategies for patients.

Methods:

We rely on a multidisciplinary approach that combine cutting-edge techniques in cellular and molecular biology, bioinformatics, mathematics and physics to address the complexity and dynamism of the cellular states that may coexist during lung tumor development and in response to treatments. We have developed this strategy though a translational perspective in close relationship with clinicians, in order to integrate in vitro, in vivo and patient data, thus reinforcing the clinical relevance of our results and facilitating the transfer of fundamental knowledge to the patients.

Key words:

  • Lung cancer,
  • Rho-GTPases,
  • cell signaling,
  • targeted therapies,
  • resistance,
  • drug-tolerance,
  • single-cell omics

Group members:

  • Célia Delahaye, Ph.D., Postdoc
  • Sarah Figarol, Pharm. D., Ph.D., Postdoc
  • Raghda Asslan, Ph.D., Postdoc
  • Sandra Pagano, PhD student, 3rd year
  • Rémi Gence, Assistant Engineer

Other team members involved:

  • Gilles Favre, Medical-Biologist, PharmD./PhD. (PU, PH)
  • Julien Mazières, M.D., Ph.D. (PU, PH)
  • Anne Pradines, Ph.D., HDR, Researcher
  • Estelle Taranchon Clermont, Engineer
  • Anne Casanova, Assistant Engineer

Main external collaborators:

  • Antonio Maraver, IRCM, Montpellier, France
  • Jacques Colinge, IRCM, Montpellier, France
  • David Santamaria, Salamanca, Spain
  • Edward Tate, Imperial College London
  • Ramón Martínez Mañez, School of Industrial Engineering, Universitat Politècnica de València, Spain

Selected publications:

Clinical cancer research: an official journal of the American Association for Cancer Research. 2014;20(24):6541-50. PMID: 25320360
Calvayrac O, Pradines A, Raymond-Letron I, Rouquette I, Bousquet E, Lauwers-Cances V, et al.
RhoB determines tumor aggressiveness in a murine EGFRL858R-induced adenocarcinoma model and is a potential prognostic biomarker for Lepidic lung cancer.

Oncogene. 2016;35(14):1760-9. (*equal contribution). PMID: 26148238
Bousquet E*, Calvayrac O*, Mazieres J, Lajoie-Mazenc I, Boubekeur N, Favre G, et al.
RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition.

Cancer research. 2016;76(6):1627-40. PMID: 26759237
Dubois F, Keller M, Calvayrac O, Soncin F, Hoa L, Hergovich A, et al.
RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non-Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway.

J Pathol. 2019;247(1):60-71. PMID: 30206932
Calvayrac O, Nowosad A, Cabantous S, Lin LP, Figarol S, Jeannot P, et al.
Cytoplasmic p27(Kip1) promotes tumorigenesis via suppression of RhoB activity.

EMBO molecular medicine. 2017;9(2):238-50. PMID: 28003335
Calvayrac O, Mazieres J, Figarol S, Marty-Detraves C, Raymond-Letron I, Bousquet E, et al.
The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism.

Med Sci (Paris). 2018 Jan;34(1):12-14. PMID: 29384086
Calvayrac O, Pradines A, Mazières J, Favre G.
The Ras-related GTPase RhoB, a relevant actor in the adaptive resistance to EGFR tyrosine kinase inhibitors in lung cancers.

Oncotarget. 2015;6(17):15250-64. PMID: 26098773
Delmas A, Cherier J, Pohorecka M, Medale-Giamarchi C, Meyer N, Casanova A, et al.
The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors.

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