Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Abstract

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF V600E -induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF V600E -driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15INK4B . This treatment also eliminated subpopulations resistant to targeted BRAF V600E inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF V600E inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.

Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma

“…However, mutational activation of BRAF in conjunction with silencing of tumor suppressors such as PTEN or CDKN2A or, as shown here, mutational activation of PIK3CA, which have no overt melanocytic phenotype on their own, allows rapid progression of BRAF V600E -initiated melanocytes to malignant melanoma. Although not explicitly examined here, these alterations presumably facilitate bypass of senescence, consistent with observations of others (59). Moreover, we have made similar observations in mouse models of BRAF V600E -induced lung or thyroid tumorigenesis (60,61).…”

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

“…Because we did not detect any cells that simultaneously displayed high levels of hTERT and low levels of HP1β, our data suggest that cancer cells emerged from HP1β-positive and therefore senescent somatic cells in analyzed lesions. This interpretation is consistent with linear melanoma and breast cancer progression models and is supported by clinical observations that certain premalignant breast and melanocytic skin lesions, which are composed of senescent cells (1), can reside nonrandomly and in close proximity to their malignant cancer counterparts (45)(46)(47)(48)(49).…”

Wnt signaling potentiates nevogenesis

“…Even so, about 25% of melanomas are thought to arise in association with a preexisting nevus (14,15). Inactivation of PTEN and p16 and activation of Wnt signaling are each thought to contribute to nevus to melanoma progression (16)(17)(18)(19). Here we investigated senescence in melanocytes in vitro and in nevi, with a view to better understand both nevus formation and progression to melanoma.…”