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

Autor:	Trieu KG; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Tsai SY; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Eberl M; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Ju V; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Ford NC; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Doane OJ; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Peterson JK; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Veniaminova NA; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Grachtchouk M; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Harms PW; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA., Swartling FJ; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 05 Uppsala, Sweden., Dlugosz AA; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA., Wong SY; Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: sunnyw@umich.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 May 03; Vol. 39 (5), pp. 110779.
DOI:	10.1016/j.celrep.2022.110779
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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