Human malignant melanoma is an aggressive cancer with high propensity for metastatic dissemination.
Despite recent advances in melanoma therapy, most patients with metastatic disease do not experience
durable benefit from current treatment options. Indeed, existing targeted and cancer immunotherapeutic
modalities do not directly inhibit tumor metastasis, which accounts for most cancer-related deaths. Accordingly,
the development of new agents that specifically target pro-metastatic pathways intrinsic to melanoma cells
could greatly improve treatment outcomes and reduce off-target toxicities. The trafficking processes observed
in disseminating metastatic cancers resemble, at least in part, the leukocyte homing paradigm, a sequential
multistep adhesive cascade involving cell tethering and rolling on microvascular endothelium, followed by
integrin-mediated arrest and transendothelial migration into secondary tissues. Leukocyte homing is dependent
on specialized integrin heterodimers and their cognate ligands on endothelial cells. To date, however,
expression of these distinct leukocytic homing integrin subsets has not been described in melanoma. Our
preliminary studies demonstrate, for the first time, aberrant expression of 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 these 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 homing integrins as novel mediators of tumor cell dissemination.
While hematopoietic 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) dissect mechanisms of melanoma cell-intrinsic
homing integrin induction and functional activation, and define integrin glycosylation states and heterodimer
composition in patient tumor biospecimens at various stages of progression, and 2) examine the therapeutic
efficacy of CRISPR/Cas-9-mediated leukocytic integrin knockout or clinical-grade integrin inhibitors originally
formulated for the treatment of immune trafficking disorders, in preclinical melanoma models. We have
assembled a team of experts in the melanoma metastasis, leukocyte homing, gene editing, dermatopathology,
and glycobiology fields, to bring to fruition the translationally relevant aims of this proposal. Results from our
studies could establish melanoma cell-expressed leukocytic integrins and their glycostructural determinants as
novel therapeutic targets for selective inhibition of metastatic dissemination.