Dynamics of nevus development implicate cell cooperation in the growth arrest of transformed melanocytes

Abstract

Mutational activation of the BRAF proto-oncogene in melanocytes reliably produces benign nevi (pigmented ‘moles’), yet the same change is the most common driver mutation in melanoma. The reason nevi stop growing, and do not progress to melanoma, is widely attributed to a cell-autonomous process of ‘oncogene-induced senescence’. Using a mouse model of Braf-driven nevus formation, analyzing both proliferative dynamics and single-cell gene expression, we found no evidence that nevus cells are senescent, either compared with other skin cells, or other melanocytes. We also found that nevus size distributions could not be fit by any simple cell-autonomous model of growth arrest, yet were easily fit by models based on collective cell behavior, for example in which arresting cells release an arrest-promoting factor. We suggest that nevus growth arrest is more likely related to the cell interactions that mediate size control in normal tissues, than to any cell-autonomous, ‘oncogene-induced’ program of senescence.

Reproduction of patterns in melanocytic proliferations by agent-based simulation and geometric modeling

“…In high density areas we also reduce the proliferation rate of melanocytes to mimic the biologic effect of contact inhibition [ 50 , 54 ]. We further configure our model in such a way that proliferation and migration degrade with higher generation numbers, which corresponds to oncogene-induced senescence in vivo [ 55 ]. As a consequence, only a limited proliferative potential [ 29 , 32 ] is available and the simulated nevus reaches a steady state and a final size as it is observed in real nevi.…”

BRAFV600Einduces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

“…The vast majority of melanocytic nevi are stably arrested and harbor BRAF V600E , an oncogenic mutation that induces cellular senescence when expressed in a variety of mammalian cells 9,12,17 . While these observations seemingly implicate OIS as the mechanism driving nevus-associated proliferation arrest, a substantial body of evidence has challenged this paradigm in recent years 8,9,[18][19][20][21][22][23][24][25] . Here, we uncover an alternative mechanism driving nevus formation and stability whereby acquisition of the BRAF V600E mutation does not necessitate proliferation arrest, but instead permits melanocytes to toggle between hyperproliferation and arrest.…”

“…Cell cycle re-entry that accompanies nevus recurrence 18 , eruption 19 , or transformation to primary melanoma suggests that the nevus arrest phenotype is reversible rather than permanent. Similarly, the expression of senescence markers do not readily distinguish human melanocytic nevi from primary or transformed melanocytes in humans (16 INK4A , TP53, H2AX and betagalactosidase) or mice (any known hallmark of senescence) 8,20,21 . Setting aside the permanence of OIS, melanocytic nevus arrest was largely thought to be driven by induction of p16 INK4A expression from the CDKN2A gene.…”

“…The BRAF V600E mutation is clonally present in ~80% of human melanocytic nevi 3 and melanocyte-specific expression of the oncogene is sufficient to induce nevus formation in mice [6][7][8] , suggesting that BRAF V600E drives proliferation arrest in melanocytes. The prevailing theory to explain this seemingly paradoxical role for BRAF V600E is oncogene-induced senescence (OIS) 9 .…”

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

“…Collectively, these data suggest that additional tumor suppressive mechanisms have the capacity to restrain the proliferation of Braf V600E -positive mouse melanocytes, independent of inducing senescence. Recent modeling studies have led to the postulation that the growth arrest of nevus melanocytes is not solely due to oncogene activation and OIS in individual cells, but rather due to cells sensing and responding to their collective overgrowth, similar to what occurs in normal tissues (25). This cell growth arrest is very reminiscent of the arrest induced by activation of the Hippo tumor suppressor pathway, which is an evolutionarily conserved pathway known to regulate organ size.…”