Basal cell carcinomas acquire secondary mutations to overcome dormancy and progress from microscopic to macroscopic disease.

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Trieu KG, Tsai SY, Eberl M, Ju V, Ford NC, Doane OJ, Peterson JK, Veniaminova NA, Grachtchouk M, Harms PW, Swartling FJ, Dlugosz AA, Wong SY

Cell Reports 39 (5) 110779 [2022-05-03; online 2022-05-05]

Basal cell carcinomas (BCCs) frequently possess immense mutational burdens; however, the functional significance of most of these mutations remains unclear. Here, we report that loss of Ptch1, the most common mutation that activates upstream Hedgehog (Hh) signaling, initiates the formation of nascent BCC-like tumors that eventually enter into a dormant state. However, rare tumors that overcome dormancy acquire the ability to hyperactivate downstream Hh signaling through a variety of mechanisms, including amplification of Gli1/2 and upregulation of Mycn. Furthermore, we demonstrate that MYCN overexpression promotes the progression of tumors induced by loss of Ptch1. These findings suggest that canonical mutations that activate upstream Hh signaling are necessary, but not sufficient, for BCC to fully progress. Rather, tumors likely acquire secondary mutations that further hyperactivate downstream Hh signaling in order to escape dormancy and enter a trajectory of uncontrolled expansion.

PubMed 35508126

DOI 10.1016/j.celrep.2022.110779

Crossref 10.1016/j.celrep.2022.110779

mid: NIHMS1804986
pmc: PMC9127636
pii: S2211-1247(22)00543-5