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

• Published in: Cell reports (Cambridge) Vol. 39; no. 5; p. 110779
• Main Authors: Trieu, Kenneth G., Tsai, Shih-Ying, Eberl, Markus, Ju, Virginia, Ford, Noah C., Doane, Owen J., Peterson, Jamie K., Veniaminova, Natalia A., Grachtchouk, Marina, Harms, Paul W., Swartling, Fredrik J., Dlugosz, Andrzej A., Wong, Sunny Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.05.2022; Elsevier
• Subjects: basal cell carcinoma; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - pathology; CP: Cancer; Gli1; Gli2; hair follicle stem cells; Hedgehog Proteins - genetics; Humans; Mutation - genetics; N-myc; N-Myc Proto-Oncogene Protein - genetics; Notch; Skin Neoplasms - genetics; Skin Neoplasms - pathology; tumor dormancy; Zinc Finger Protein GLI1 - genetics; tumor dormancy; CP: Cancer; Notch; hair follicle stem cells; basal cell carcinoma; N-myc; Gli1; Gli2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110779

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. [Display omitted] •Upstream Hh pathway activation is necessary, but not sufficient, for BCCs to progress•Failed nascent tumors become dormant and may spontaneously regress over time•Secondary mutations enable rare tumors to overcome barriers to progression•Increased Mycn promotes BCC progression Trieu et al. generate BCC mouse models in which rare macroscopic tumors form alongside numerous failed microscopic lesions. Successful macroscopic tumors acquire secondary changes that elevate Gli1, Gli2, and/or Mycn levels, causing hyperactivation of downstream Hedgehog (Hh) signaling. Loss of p53 and Notch1 also contributes to tumor progression.