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Melanoma Senescence

Senescence is viewed as permanent cell-cycle arrest brought about by a variety of different mechanisms. The first observed and reported in the early 1960s is replicative senescence, which is primarily driven by telomere shortening due to cell division. Many other, telomere independent paths to senescence were reported in the following decades, including oncogene-induced senescence (OIS), oncogene inactivation-induced senescence (OIIS), senescence due to oxidative stress as well as DNA damage, and different flavors of premature senescence. It is now widely accepted that many of these routes to senescence have molecular overlaps.

Morphologically, senescent cells share several characteristics: Cells i) are enlarged flattened, and rich of cytoplasmic vacuoles ii) show beta-galactosidase reactivity (which is widely used as a histological marker of senescent cells) iii) lack the expression of proliferative markers, and iv) display the presence of specific heterochromatin foci responsible for epigenetic silencing of targets mediating proliferation. Melanocytic nevi are a model-system of OIS: A proliferative stimulus in a melanocyte, mediated by activating mutations in BRAF and NRAS, leads to increased proliferation, which is rescued by ‘protective’ senescence. The majority of nevi and melanomas share these genetic drivers in the MAP-kinase pathway, which is why they are believed to be early events in melanomagenesis. However, progression of a nevus to a melanoma is a rare event, highlighting that cellular senescence is a powerful mechanism to suppress (further) tumor formation.  It is technically challenging to capture the progression of a nevus to a melanoma in vivo, but about 30% of all melanomas contain remnants of nevi upon histology. The remaining melanomas arise on otherwise healthy skin.

In this project we aim at identifying molecular and (epi)genetic mechanisms of melanomagenesis in nevus-associated melanoma patients. 

© 2020 by Posch-lab

Video by Alex T.Ritter/NIH Oxford-Cambridge Scholars