Functional Analysis of a Novel Integrin-Dependent Metastasis Pathway in Melanoma

• Applicant: Dr. Erik Rasbach
• Subject Area: Dermatology ; General and Visceral Surgery
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470684420

Malignant melanoma is a highly aggressive cancer with high propensity for metastatic disease. Despite recent therapeutic advances, melanoma mortality remains high due to limited responses and acquired resistance mechanisms. Current treatment strategies mainly target melanoma susceptibility or immune escape pathways, but not specifically metastatic processes responsible for most cancer-related deaths. Accordingly, the development of new agents that specifically target the metastatic machinery could greatly improve treatment outcomes and reduce off-target toxicities. There are striking parallels between cancer cell metastasis and leukocyte homing mechanisms. Indeed, increasing evidence suggests that pro-metastatic melanoma cell subsets might highjack leukocyte-specific trafficking mechanisms to home to distant tissues. Integrins represent a superfamily of heterodimeric adhesion and signaling receptors acting as key regulators of leukocyte migration. Members of the β2 integrin superfamily, in particular, govern leukocyte migration via interaction with intercellular adhesion molecules (ICAMs). However, β2 integrin functions have hitherto not been studied in melanoma cells.Preliminary studies performed by the Schatton laboratory demonstrate, for the first time, aberrant expression of such β2 integrin heterodimers, conventionally thought to be restricted to leukocytes, by melanoma cell subsets with high metastatic capacity. In patient primary melanomas, cancer cell-intrinsic integrin positivity correlated with sentinel lymph node metastases. Melanoma-specific inhibition of β2 integrin heterodimers suppressed endothelial adhesion and significantly blocked growth and metastasis formation in preclinical mouse models of human melanoma. These paradigm-shifting findings identify leukocytic β2 homing integrins as novel mediators of tumor cell dissemination.While β2 integrin targeting approaches, including humanized antibodies, have already been developed for the treatment of patients with inflammatory and autoimmune leukocyte trafficking disorders, they have never been examined in the context of cancer. In this proposal, we newly investigate the therapeutic utility of these validated and readily available integrin inhibitors in blocking metastatic dissemination in preclinical melanoma models. Our specific aims are to (1) define β2 frequency, composition, and glycostructures during clinical melanoma progression, and (2) examine the therapeutic efficacy of β2 integrin interference in preclinical melanoma models. Novel research insights generated as part of this proposal could be rapidly translated from bench to bedside, since β2 and αL integrin blockers are readily available for patient use. Given that tumoral β2 expression has been detected in additional malignancies, albeit with ill-defined in vivo function, the proposed research initiative has broad implications for both basic β2 biology and therapy of multiple cancer types.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Tobias Schatton, Ph.D.