Dynamics of nevus development implicate cell cooperation in the growth arrest of transformed melanocytes
Rolando Ruiz-Vega,
Chi-Fen Chen,
Emaad Razzak,
Priya Vasudeva,
Tatiana B Krasieva,
Jessica Shiu,
Michael G Caldwell,
Huaming Yan,
John Lowengrub,
Anand K Ganesan,
Arthur D Lander
Affiliations
Rolando Ruiz-Vega
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
Chi-Fen Chen
Department of Dermatology, University of California, Irvine, Irvine, United States
Emaad Razzak
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
Priya Vasudeva
Department of Dermatology, University of California, Irvine, Irvine, United States
Tatiana B Krasieva
Beckman Laser Institute, University of California, Irvine, Irvine, United States
Jessica Shiu
Department of Dermatology, University of California, Irvine, Irvine, United States
Michael G Caldwell
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
Huaming Yan
Department of Mathematics, University of California, Irvine, Irvine, United States
John Lowengrub
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States; Department of Mathematics, University of California, Irvine, Irvine, United States
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States; Department of Dermatology, University of California, Irvine, Irvine, United States
Center for Complex Biological Systems, University of California, Irvine, Irvine, United States; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States; Department of Biological Chemistry, University of California, Irvine, Irvine, United States
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.
