Metastatic Melanoma - U.S. Department of Veterans Affairs

Proximity of immune and tumor cells underlies response to BRAF/MEK-targeted therapies in metastatic melanoma patients.

Tumor cell cellularity increased in the TCGA-melanoma cohort to predict overall survival in patients with early-stage melanoma.

Source link: https://doi.org/10.1038/s41698-021-00249-1

Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.

A 32-gene signature for which reduced expression is strongly associated with lung metastatic risk is found in RNA-seq analysis of transcriptomes from HP and HPN primary melanomas. The silencencing of three representative HPN lung metastasis signature genes in human melanoma cells resulted in higher invasive activity, consistent with these genes' roles as mediators of NME1 and NME2's metastasis suppressor function. In conclusion, our research has found a family of genes that mediate suppression of melanoma lung metastasis, as well as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma.

Source link: https://doi.org/10.1038/s41388-021-01998-w

EPAC-RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP.

Although mutations in MAPK pathway genes are the most common oncogenic agents of melanoma, mutations in MAPK pathway genes are among the most common oncogenic causes of melanoma, the role of cAMP in melanoma is not well understood. The measurement of pERK levels revealed that this phenotypic shift was not linked to changes in MAPK pathway activity. Although cAMP elevation did not raise the sensitivity of metastatic melanoma cells to BRAF and MEK inhibitors, the EPAC-RAP1 axis seems to have contributed to resistance to MAPK pathway inhibition. These results show a MAPK pathway-independent change in response to cAMP signaling during melanoma progression. Implications: These results reveal a pro-independence mechanism that involves the cAMP-EPAC-RAP1 signaling pathway, which may lead to the development of novel melanoma therapies.

Source link: https://doi.org/10.1158/1541-7786.MCR-17-0067

NLRP1 promotes tumor growth by enhancing inflammasome activation and suppressing apoptosis in metastatic melanoma.

The presence of NLRP1 expression in melanoma was confirmed by analysis of 216 melanoma tumors and 13 human melanoma cell lines. Unlike monocytic THP-1 cells with high nuclear localization of NLRP1, melanoma cells expressed NLRP1 mainly in the cytoplasm. However, NLRP1 in melanoma behaved differently in the context of cell death than previous findings, enhancing pyroptosis in macrophages. Immunoprecipitation demonstrated contact between NLRP1 and CARD-containing caspase-2 and -9, whereas NLRP3 lacking a CARD motif did not interact with the caspases. NLRP1's activation and apoptosis through contacts with caspase-2, -9, and -9 were consistent with these findings; but not NLRP3 stimulation resulted in caspase-3/7 activation and apoptosis in human melanoma cells, but not NLRP3 activation or initiation.

Source link: https://doi.org/10.1038/onc.2017.26

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