mTORC1 Activation Blocks BrafV600E-Induced Growth Arrest but Is Insufficient for Melanoma Formation

Abstract

SUMMARY BrafV600E induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in BrafV600E melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100 which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth-arrest of BrafV600E melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in BrafV600E melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis.

Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming

“…4). A previous report in a melanoma progression transgenic mouse model also found increased mTORC1 signaling upon Cdkn2a knockout due to miR-99/100 (Damsky et al, 2015). Our data indicate that ATR signaling regulates mTORC1 activation (Fig.…”

Expression of oncogenic BRAFV600E in melanocytes induces Schwannian differentiation in vivo

“…This Schwannian phenotype was indeed a consequence of the BRAF V600E in vivo , as all the masses stained positive for BRAF V600E protein (Figure 1G). This finding was not an artifact of insertional effects in the 470 BRAF V600E line, as similar tumors were present in the 476 line in the context of Arf or Cdkn2a loss (Figure 1H), and Schwannian-like differentiation was also reported in other melanoma models in which the BRAF V600E is expressed from the endogenous locus (Marsh Durban et al, 2013, Damsky et al, 2015). Intriguingly, the Schwannian masses seldom progressed to malignancy, remaining benign for the life-span of the animals, suggesting the trans-lineage differentiation between melanocytes and Schwann cells is tumor suppressive, supplementing senescence to inhibit melanoma formation in response to BRAF V600E .…”

Forging a signature of in vivo senescence

“…Human and mouse melanocytes form growth-arrested naevi in response to oncogene activation (through BRAF-V600E), and these naevi are characterized by the expression of several markers of senescence, such as SAβ-gal and p16 INK4A (REFS 152,153). However, in mice, these apparently senescent melanocytes can be readily coaxed back into the cell cycle 154,155 . An alternative interpretation is that p16 INK4A is activated by BRAF-V600E to provide a barrier to malignant transformation, and that unrelenting oncogenic RAF signalling and the deranged tissue architecture present in a naevus in turn cause the production of senescence markers, including SAβ-gal and inflammatory cytokines, through activation of established pathways, such as those dependent on NF-κB.…”