
Intracellular signaling modules linking DNA damage to secretome changes in senescent melanoma cells
Author(s) -
Alexandra Chavanet,
Kathryn R. Hill,
Yanek Jiménez-Andrade,
MinKyung Choo,
Kristin White,
Jin Mo Park
Publication year - 2020
Publication title -
melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.072
H-Index - 73
eISSN - 1473-5636
pISSN - 0960-8931
DOI - 10.1097/cmr.0000000000000671
Subject(s) - senescence , biology , melanoma , dna damage , microbiology and biotechnology , carcinogenesis , intracellular , signal transduction , cancer research , cancer , genetics , dna
Cellular senescence is a major barricade on the path of cancer development, yet proteins secreted from senescent cells exert complex and often discordant effects on subsequent cancer evolution. Somatic genome alternations driving the formation of nevi and melanoma are efficient inducers of cellular senescence. Melanocyte and melanoma cell senescence is likely to come into play as a key factor affecting the course of tumorigenesis and responsiveness to therapy; little mechanistic information has been generated, however, that substantiates this idea and facilitates its clinical translation. Here, we established and characterized a model of melanoma cell senescence in which pharmacologically induced DNA damage triggered divergent ATM kinase- and STING-dependent intracellular signaling cascades and resulted in cell cycle arrest, cytomorphologic remodeling, and drastic secretome changes. Targeted proteome profiling revealed that senescent melanoma cells in this model secreted a panoply of proteins shaping the tumor immune microenvironment. CRISPR-mediated genetic ablation of the p38α and IKKβ signaling modules downstream of the ATM kinase severed the link between DNA damage and this secretory phenotype without restoring proliferative capacity. A similar genetic dissection showed that loss of STING signaling prevented type I interferon induction in DNA-damaged melanoma cells but otherwise left the senescence-associated processes in our model intact. Actionable proteins secreted from senescent melanoma cells or involved in senescence-associated intracellular signaling hold potential as markers for melanoma characterization and targets for melanoma treatment.