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, e.g. 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.

The role of PI3'‐lipid signalling in melanoma initiation, progression and maintenance

“…Consistent with this, numerous studies have demonstrated that expression of BRAF V600E in mouse melanocytes can generate melanocytic nevi with signs of senescence in vivo , or promote senescence of cultured human melanocytes in vitro 21,22 . However, more recent data analysing mRNA expression data have called into question whether such melanocytic nevus cells are indeed senescent 23 . Regardless of senescence, a consensus has emerged that melanomagenesis requires multiple cooperating events in which mutational activation of BRAF or NRAS may serve as a foundation upon which additional events accumulate.…”

Multi range ERK responses shape the proliferative trajectory of single cells following oncogene induced senescence

“…It is also important to note that our gene classes are not exhaustive and that additional types of regulations (e.g., protein levels or post-translational modifications) must co-exist for a robust bell-shaped proliferation response. For instance, high ERK activity can prevent cell cycle progression by inducing degradation of key regulators (Deschênes-Simard et al, 2013), by modulating senescence-associated secretomes (Di Mitri and Alimonti, 2016) or by engaging homeostasis at tissue levels (Ruiz-Vega et al, 2020). We envision a broader set of genes and diverse regulatory mechanisms are needed for cells to engage a robust and coherent bell-shape proliferation response.…”

“…It remains unclear why a subset of cells in a population is better able to tolerate the negative effects of oncogene activation. Contributing factors are likely to include the type, strength and duration of the senescence-inducing signal, non-cell autonomous influences from oncogene expression, and the susceptibility of a cell to (epi)genetic reprogramming (Adams, 2009; Ruiz-Vega et al, 2020).…”

Cancer progression as a learning process

“…OIS is usually depicted as a cell-autonomous stress response, namely, expressing an oncogene in a cell leads to stress which induces a growth arrest in that cell. However, a recent study by Ruiz-Vega et al (Ruiz-Vega et al, 2020), using a mouse model of BRAF-driven nevus formation, showed that this is not necessarily the case. BRAF mutation is the most common driver mutation in melanoma (Davies et al, 2002), yet it is present in 89% of benign nevi (pigmented ''moles'') (Pollock et al, 2003).…”