Microenvironment-derived factors driving metastatic plasticity in melanoma

Abstract

Cellular plasticity is a state in which cancer cells exist along a reversible phenotypic spectrum, and underlies key traits such as drug resistance and metastasis. Melanoma plasticity is linked to phenotype switching, where the microenvironment induces switches between invasive/MITFLO versus proliferative/MITFHI states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITFHI/differentiated/proliferative state. Zebrafish imaging demonstrates that after extravasation, melanoma cells become pigmented and enact a gene expression program of melanocyte differentiation. We screened for microenvironmental factors leading to phenotype switching, and find that EDN3 induces a state that is both proliferative and differentiated. CRISPR-mediated inactivation of EDN3, or its synthetic enzyme ECE2, from the microenvironment abrogates phenotype switching and increases animal survival. These results demonstrate that after metastatic dissemination, the microenvironment provides signals to promote phenotype switching and provide proof that targeting tumour cell plasticity is a viable therapeutic opportunity.

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

“…Both responses are intensely energy-intensive, and it has been speculated that tumors can undergo dynamic cycles of each process, but not both at the same time in a mechanism called cell proliferation-motility dichotomy (9), or phenotype-switching (10). Although this process may dictate metastatic competence and ultimately influence disease outcome, its mechanistic underpinnings (9) have remained elusive (11), with only a handful of regulators of cell cycle transitions (12), transcriptional (13) and translational (14) programs, and membrane dynamics of cell motility (15) potentially implicated in phenotype switching (16).…”

Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study

“…Moreover, TYR pigmentation, melanosome transfer, and phagocytosis of melanosomes by keratinocytes are enhanced in the presence of keratinocyte‐derived growth factor, SCF . On the other hand, the addition of 12‐0‐tetradecanoylphorbol acetate (TPA), cholera toxin (CT), isobutylmethylxanthine (IBMX), and bFGF NHM growth medium led to an increase in intracellular cAMP level and melanocyte proliferation …”

“…Melanin synthesis could be enhanced with the addition of nutrients such as l ‐tyrosine and l ‐glutamine . Glucose and l ‐glutamine may affect growth of melanoma cell/cell lines to provide proliferation of melanoma cell lines . It is worthy to note that melanoma cell line does not exhibit anchorage‐dependent or density‐dependent inhibition.…”

“…It is worthy to note that melanoma cell line does not exhibit anchorage‐dependent or density‐dependent inhibition. Hence, it continues to divide well beyond monolayer, forming clump of overlapping cells …”

“…Special standard testing of pigmentary regulators (STOPR) protocol using immortalized melan‐a melanocytes was previously developed and proposed for high sensitivity and consistent effect of cell proliferation, differentiation, and results . Other melanoma cells (ie, SK‐MEL‐2) and transfected cells SH‐SY5Y, P‐MDCK, and PC12 have also been used for depigmenting activity determination due to the presence of TYR activity and melanin‐producing ability . Nevertheless, these cells were often used for cancer‐drug screening, neuron study, blood‐retinal barrier evaluation, and other structure‐molecular studies.…”