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Targeting melanoma cell-intrinsic beta2 integrin inhibits ICAM-1-mediated tumor progression

ABSTRACT: Integrin b2 is an essential mediator of immune cell activation and trafficking via interaction with intercellular adhesion molecule (ICAM)-1. Expression of b2 integrins is thought to be restricted to cells of the hematopoietic lineage. Here we demonstrate nonhematopoietic expression and CD44-dependent induction and activation of integrin b2 by malignant melanoma cells. Tumor cell-b2 in patient primary melanomas correlates with sentinel lymph node metastases, mediates adhesion to ICAM-1, and promotes tumor progression in preclinical models of human and murine melanoma. Consistently, inhibition of melanoma cell-intrinsic b2 integrin using blocking antibodies or CRISPR/Cas9-based b2 gene knockout potently suppresses ICAM-1-dependent melanoma cell adhesion, tumor growth, and metastatic dissemination. Melanoma cell-b2:ICAM-1 interaction stimulates downstream Wnt pathway components, including non-canonical Wnt5a, the pharmacologic inhibition of which reverses protumorigenic melanoma-b2 integrin activity. This work identifies a tumor cell-intrinsic integrin b2:ICAM-1 protumorigenic axis as a bona fide cancer therapeutic target in melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE261845 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Introduction Metastatic potential and rising incidence make cutaneous melanoma a major health concern worldwide. Although the therapies currently in use have proven effective, their use is limited by side effects arising and development of drug resistance. For this reason, research for new therapeutic targets and predictive biomarkers is crucial. Semaphorin 5A (SEMA5A) is a member of the Semaphorin family with involvement in cancer biology and neural development. We previously demonstrated that this protein promotes different in vitro melanoma aggressive features. In this work we further investigated the role and the mechanism of action of SEMA5A in melanoma formation and progression. Methods We performed proteomic analysis of stable knockdown SEMA5A human melanoma cells, and in silico analysis to identify cellular pathways modulated by SEMA5A. In vitro clonogenic assay and cell viability assay under different substrate conditions were conducted by using both human and murine melanoma SEMA5A knockdown clones. Western blotting analysis and immunofluorescence have been employed to investigate focal adhesion pathway regulation and lamellipodia formation after SEMA5A depletion. Nocodazole assay was used to evaluate focal adhesion dynamic. Xenograft mouse model of melanoma was used to investigate the effect of SEMA5A depletion in tumor formation and growth. Results Ingenuity pathway analysis showed that SEMA5A effects several different cellular pathways essential for cell viability, cell proliferation, and cytoskeletal dynamics, including focal adhesion and lamellipodia formation. We demonstrated that SEMA5A depletion reduced clonogenic properties and cell viability of cells in both low and high stiffness condition of culture. SEMA5A affected Focal adhesion kinase and Paxillin phosphorylation, integrin beta 1 activation, thus regulating focal adhesion dynamics, and lamellipodia formation, regulating Arp3 nucleation and expression. Delay of tumor formation and reduced tumor growth was observed in mice bearing tumor expressing low level of SEMA5A. Conclusions These findings demonstrate that SEMA5A is a novel player of melanoma aggressiveness and progression, being involved in modulating cell viability, focal adhesion signaling and lamellipodia in vitro and tumor growth in vivo.

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Targeting melanoma cell-intrinsic beta2 integrin inhibits ICAM-1-mediated tumor progression

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