Highlights in Cancer Research: May 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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6. Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion

Ablain, J. et al. Nat Genet. 54: 1839–1852 . (2022).
doi: 10.1038/s41588-022-01191-z.

Summary of the findings

Our understanding of the mechanisms driving tumor dissemination is still incomplete, especially in non-epithelial tumors like melanoma. Only few genetic alterations have been shown to promote metastasis and non-genetic events have emerged as major contributors to cancer cell spreading. Here, we describe a cooperation between external stress and genetic abnormalities in the regulation of melanoma metastasis. We identified deletions of the adhesion gene NECTIN1 in approximately half of human melanomas and found that NECTIN1 levels were lower in metastases than in primary tumors. Through experiments in cell lines, zebrafish models and human melanoma samples, we discovered that NECTIN1 loss promotes melanoma dissemination specifically in response to a local drop in insulin-like growth factor 1 (IGF1) concentration. NECTIN1 is required for the formation of adherens junctions, cell-cell contacts typical of epithelial tissues. Surprisingly, IGF1 depletion elicited the robust formation of adherens junctions between NECTIN1-wildtype melanoma cells, suggesting that non-epithelial tumors can form epithelial structures under stress. In contrast, NECTIN1-deficient cells failed to establish these junctions and, instead, activated a cell-matrix adhesion program triggering their migration. These findings uncover a mechanism by which genetic alterations in cell-cell adhesion modulate the response of cancer cells to microenvironmental stress, thus controlling their metastatic behavior.

Future impact

Model for the role of NECTIN1 loss in melanoma dissemination. Image created with Biorender.

Recent evidence suggests a substantial overlap between the migratory state of cancer cells and the resistance to current anti-proliferative drugs. Our results indicate that the migratory state of cancer cells is regulated by a combination of different signals from their microenvironment, including chemical cues, such as growth factors, and physical conditions, such as the presence of neighboring cells to which they can adhere. A deeper understanding of the multiplicity of these signals and their associated pathways inside cancer cells may reveal new therapeutically actionable vulnerabilities of metastatic tumors.