Gap Junction–Mediated Communication in Melanoma - From Tumor Progression to Treatment Response

Sep 23, 2026

Uploaded by James

Melanoma is a highly malignant skin neoplasm marked by early metastasis and rising global incidence. Despite therapeutic advances in immunotherapy, including PD-1 and CTLA-4 checkpoint inhibitors, treatment-related toxicities, heterogeneous responses, and drug resistance remain major barriers. This review focuses on gap junction proteins, connexins, highlighting stage-dependent regulation during melanoma progression and their dual behavior as tumor suppressors in early development and enhancers of metastasis in late disease.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages27

Reading Time1 h 8 min

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Melanoma Progression—Limitations of Current Therapies

Epidemiology and Public Health Burden of Melanoma

Genetic Drivers and Environmental Risk Factors

Melanoma Staging and Prognostic

Review Gap Junction–Mediated Communication in Melanoma: From Tumor Progression to Treatment Response Juliana Massoud†, Sarah Ibrahim†, Madison Jensen, Michael C. Beary, Ben Nafchi, Michael Springer and Shoshanna N. Zucker * Academic Editor: Michael Eccles Received: 3 January 2026 Revised: 23 February 2026 Accepted: 26 February 2026 Published: 16 March 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. D’Youville University School of Pharmacy, D’Youville University, 320 Porter Avenue, Buffalo, NY 14201, USA; [massoj15@dyc.edu](massoj15@dyc.edu) (J.M.); [ibras09@dyc.edu](ibras09@dyc.edu) (S.I.); [jensem29@dyc.edu](jensem29@dyc.edu) (M.J.); [bearym23@dyc.edu](bearym23@dyc.edu) (M.C.B.); [alimob19@dyc.edu](alimob19@dyc.edu) (B.N.); [sprinm22@dyc.edu](sprinm22@dyc.edu) (M.S.) * Correspondence: [zucker@dyc.edu](zucker@dyc.edu) † These authors contributed equally to this work. Abstract Melanoma is a highly malignant neoplasm of the skin with early metastatic spread and increasing incidence worldwide. Although there are significant therapeutic advances in immunotherapy, especially with the checkpoint inhibitors targeting PD-1 and CTLA-4, challenges such as treatment-related toxicities, a heterogeneous response to therapy, and drug resistance continue to exist. There are unmet needs for novel therapeutic strategies and/or approaches to complement the existing treatment options. Potential targets for future melanoma treatment are the gap junction proteins, connexins, which show an altered pattern of regulation during melanoma progression. In this review, we highlight the regulation of gap junctions during melanoma progression and the characterization of gap junctionsas tumor suppressors during early-stage tumor development and then the reversion to enhancers of tumor metastasis during late-stage melanoma progression. We provide a comprehensive overview of gap junctions in the skin and how the connexin proteins, which comprise gap junctions, are alternatively regulated in melanoma progression. Connexins are protein channels in the human body that consist of 21 isoforms. These isoforms form gap junctions that provide important intercellular signaling and permeability channels. Each connexin protein consists of four transmembrane domains and a C-terminal tail, which is an important part of its function and regulation. Permeants of gap junctions include signaling molecules such as cyclic AMP and inositol triphosphate which are linked to key cellular behaviors such as proliferation and migration, making them essential for several tumor-related processes. At least ten connexin isoforms are found in normal skin. Connexin 43 (Cx43) is classified as the most prevalent isoform while Connexin 26 (Cx26) has been reported to be more specialized with restricted expression patterns. Cx43 and Cx26 regulate the growth, differentiation, and repair of the epidermis after injury. Evidence suggests that connexins have a stage-related function in melanoma. Loss of connexin expression and gap junctional intercellular communication is linked to tumor suppression and loss of differentiation in early-stage melanoma, while re-expression or overexpression of specific connexins, notably Cx43, may promote metastasis through enhanced tumor–stromal interactions and increased motility in late-stage melanoma. Such opposing actions of connexins support their candidacy as biomarkers and therapeutic targets. Understanding the dual-stage related functions of connexins in melanoma development and progression may lead to less cytotoxic and more efficient future therapeutic approaches. Keywords: melanoma; gap junctions; connexins; tumor progression 1. Melanoma Progression—Limitations of Current Therapies 1.1. Epidemiology and Public Health Burden of Melanoma Melanoma represents a clin

FAQs

What challenges limit current melanoma immunotherapies?

Even with checkpoint inhibitors targeting PD-1 and CTLA-4, treatment-related toxicities, heterogeneous response, and drug resistance persist.

What are connexins and why are they important in melanoma?

Connexins are the protein channels that form gap junctions, enabling intercellular signaling and permeability that influence tumor-related processes such as proliferation and migration.

How do connexins function differently across melanoma stages?

The review describes a loss of connexin expression and gap junction communication in early-stage melanoma associated with tumor suppression and differentiation loss, while later-stage re-expression/overexpression of specific connexins (notably Cx43) may promote metastasis through tumor–stromal interactions and motility.

Sep 23, 2026

Uploaded by James