Microenvironment, signaling and cancer

Previous activities

The tumor microenvironment regulates cancer progression through complex and dynamic interactions between tumor cells, activated stromal cells and components of the extracellular matrix, creating a co-evolving ecosystem. Stromal cells usually include tumor-associated fibroblasts, endothelial cells, and infiltrating inflammatory and immune cells. The communication between cancer cells and its stroma in a tumor not only alter the biological properties of the cancer cell, but also of the different cells in the stroma, promoting tumor growth, metastasis and resistance to therapeutics. Understanding how the tumor ecosystem fosters malignant growth, invasion and metastasis cascade should open up new avenues for stroma-targeted therapies for cancer. Our laboratory is interested in the crosstalk between cancer cells and their stroma within the lymph node microenvironment in two tumor models, melanoma, an aggressive clinical form of skin cancers and lymphoma. The lymph node is the first locus of expansion for invasive melanoma cells and one of the natural niches of malignant B-cells.
In a first axis, we are following up our work on the molecular and cellular mechanisms governing melanoma development with a particular focus on SPARC, a matricellular protein that modulates the dialogue between tumor cells and their stroma. Our lab achieved important discoveries such as: (i) the role of SPARC as a matricellular regulator of Epithelial Mesenchymal Transition (EMT) and p53-dependent cell survival; and (ii) the epigenetic silencing of the tyrosine kinase Syk and its contribution in melanoma senescence bypass, Kit signaling and metastasis. Ongoing projects in the lab are pursuing our initial results on SPARC and Syk using different mouse melanoma models and the study of the role of tumor-associated fibroblasts within the lymphatic metastatic niche in survival and therapeutic resistance. Our aim is to translate our results on melanoma to the clinic.
The second axis is devoted to the understanding of the molecular and cellular mechanisms involved in the environment-mediated cell death resistance observed in multiple lymphoid malignancies. Our past studies on the signaling pathways downstream Syk family kinases in normal and pathological leukocytes led to : (i) the characterization of several Syk effectors, including the Rho GTPases activators VAV and the adapter 3BP2; (ii) the identification in chronic lymphocytic leukemia of a Syk-PI3K-Akt axis involved in chemokine-induced and FOXO3-dependant cell survival and in the proteasome-mediated regulation of the antiapoptotic protein Mcl-1. Current projects aim at deciphering how extracellular proteins such as SPARC and stromal cells impact on lymphoid malignancies resistance to cell death and treatment.

Our work would have strong relevance with respect to the dynamic and reciprocal interactions between cancer cells and their microenvironment and would bring a better understanding of melanoma and lymphoma malignancies and of the biology of the lymphatic system in cancer and metastasis. Beyond their cognitive aspect on signaling pathways that control the pathological cell-cell and cell-matrix communication within the tumor microenvironment, our findings would have important implications for identification of novel biomarkers for invaded lymph nodes and potential targets, and improvements of the clinical management of the diseases.

Team Publications