Adhesion and signaling in metastatic melanoma

Context and objectives

The “Adhesion and Signaling in Metastatic Melanoma” research team is committed to uncovering new vulnerabilities of cancer cells through a better understanding of the mechanisms underlying two critical aspects of tumor biology: 1) initiation and maintenance, 2) metastatic progression.

• Initiation and maintenance

Hyperactivation of the MAPK pathway is responsible for the formation and development of many tumor types. Melanoma, the deadliest form of skin cancer, is the archetype of MAPK-driven cancer, as all melanomas harbor genetic alterations resulting in constitutive activation of this pathway. Targeted therapies that block this pathway have demonstrated clinical efficacy, but their impact is limited by the development of resistance. Identifying new targets in this pathway could thus improve current treatments. We have previously established the function of a little-known regulator of the MAPK pathway, SPRED1, in melanoma. Our goal is to discover new regulators of the MAPK pathway with therapeutic potential in melanoma.

• Metastatic progression

Tumor metastasis is the leading cause of mortality for patients with cancer. Yet, no approved therapy currently targets the spreading capacity of cancer cells. In melanoma, the presence of metastases is associated with very poor survival despite the efficacy of current treatments. We hypothesize that better understanding the mechanisms underlying tumor dissemination will reveal unsuspected vulnerabilities of aggressive cancers. The tumor microenvironment has emerged as a major regulator of cancer cell behaviors. However, its influence on tumor dissemination remains obscure. We have recently identified a cooperation between local levels of the growth factor IGF1 and the ability of tumor cells to form cell-cell junctions in the regulation of metastatic spread in melanoma. We now aim to uncover other microenvironment-sensing mechanisms controlling melanoma dissemination, with the long-term goal of defining new vulnerabilities of metastatic cancer cells.

Approaches and projects

We combine mechanistic studies in human melanoma cell lines with powerful genetic manipulation techniques in zebrafish and analyses in clinical specimens to investigate the role of candidate regulators of tumor initiation, maintenance, and metastatic progression. We use all relevant biochemistry, cell biology, and molecular biology techniques to define the function of our regulators of interest in human cells in vitro, including in 3D models of human skin. We also leverage the powerful genetics and unparalleled imaging capabilities of zebrafish to investigate these mechanisms in vivo. A well-established model of primary melanoma in adult zebrafish faithfully recapitulates the genetics of the human disease in a relatively short time-frame. We combine high-throughput genetic manipulation with cutting-edge live-imaging in zebrafish melanomas to probe candidate genes and witness changes in cancer cell behaviors in situ. In addition, this model is amenable to drug treatment, enabling pharmacological and preclinical studies. Finally, we have access to samples of human melanoma through a collaboration with the Onco-dermatology Unit of Hospices Civils de Lyon. Analysis of these samples allows us to either generate new hypotheses or validate our findings in human.

Projects currently developed in our laboratory include:

• Elucidating and targeting the mechanism by which local IGF1 signaling regulates adherens junction formation and melanoma cell migration;
• Identifying new clinically-relevant cell-surface sensors controlling melanoma dissemination with a high-throughput genetic screen in adult zebrafish;
• Defining cell communication between melanoma and niche cells involved in metastatic progression using single-cell transcriptomics in human melanoma samples;
• Investigating the role of a new regulator of the MAPK pathway in melanoma cell maintenance.

Our research program will greatly improve the current understanding of the molecular mechanisms driving tumor maintenance and metastatic progression, with the long-term objective to develop innovative therapies against aggressive cancers.