Research Team 2 – INSERM UMR 1033

Bone, Cancers and Metastases

Long before the development of clinically detectable bone metastases, circulating tumour cells disseminate in the bone marrow where they create a cancer niche that is conducive to their survival and subsequent growth. Experimental models have provided insights into the genetic basis of metastasis, identifying specific cancer cell « gene signatures » that correlate with metastasis in specific organs, such as bone, brain, and lungs. Yet, how tumour cells acquire these metastatic traits has remained obscure. Similarly, the identity of the subsets of tumour cells that manage to survive in the bone marrow and achieve overt metastases remains largely unknown. Thus, in order to prevent bone metastases, there is an urgent need to identify oncogenic drivers and epigenetic regulators of metastasis genes that predispose these subsets of tumour cells to disseminate in the bone marrow. We will study the roles of axonal roundabout (ROBO) receptors, the zinc finger protein 217 (ZNF217) oncogene and microRNAs as major drivers and/or epigenetic regulators that control the metastasis-initiating capacities of breast cancer cells to bone. Furthermore, microRNAs can also be released into the circulation from tumour cells, either free or contained within vesicles called exosomes. These circulating microRNAs are remarkably stable and can serve as inter-cellular messengers following uptake by bone cells and reprogram or educate recipient cells to facilitate bone metastasis formation by creating a cancer niche. We will identify and study the functions of microRNAs that regulate the construction of this cancer niche and determine whether these microRNAs may be used as biomarkers to predict bone relapse in patients with breast cancer. Similarly, the biomarker value of ZNF217 and its variants in predicting bone metastasis occurrence will be evaluated.

Immunotherapies have shown unprecedented promise in the clinic, dramatically increasing overall survival of patients with advanced-stage cancers (e.g., melanoma, NSCLC). The benefit of these immunotherapies on treatment of patients with advanced cancer and bone metastases remains however largely unknown. Moreover, immune checkpoint inhibitor (ICI) therapy may be associated with inflammatory arthritis, which could be deleterious for patients with bone metastases. To address this question, we will characterize the local determinants of inflammation in bone metastases and develop a syngeneic animal model of NSCLC bone metastasis to evaluate the effects of immune modulators that are used to treat arthritis-related adverse events induced by ICI therapy.

The evaluation of the fracture risk of metastatic bone lesions in patients with advanced cancer is a major challenge. Half of the patients with bone metastasis will experience skeletal complications. We will develop finite element analysis (FEA)-based techniques to investigate mechanical properties of experimental bone metastases and of metastatic bones (femur and vertebrae) from patients with advanced cancer, so we will then be able to predict the fracture risk in patients with bone metastases.

These projects are funded by grants obtained from INSERM (REMOTE), the University of Lyon, the University of Sheffield, highly selective French national research programs (the laboratory of excellence LabEx DEVweCAN and PRIMES), charities (Ligue contre le Cancer, Weston Park Cancer Charity), MSD Avenir, the Région Auvergne-Rhône-Alpes (Pack Ambition International), the French Embassy in Hanoi, Vietnam, and the Cancer Institute (iC-HCL) from Hospices Civils de Lyon.



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