Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Rep. 2022 May 3;39(5):110779. 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.
基底细胞癌（BCC）常具有巨大的突变负担；然而，这些突变中的大多数的功能意义尚不清楚。在这里，我们报告了 Ptch1 的缺失，即激活上游 Hedgehog（Hh）信号的最常见突变，会引发新生的类似 BCC 的肿瘤的形成，这些肿瘤最终进入休眠状态。然而，少数能够克服休眠的罕见肿瘤通过多种机制获得了过度激活下游 Hh 信号的能力，包括 Gli1/2 的扩增和 Mycn 的上调。此外，我们证明 MYCN 的过表达促进了由 Ptch1 缺失诱导的肿瘤的进展。这些发现表明，激活上游 Hh 信号的经典突变对于 BCC 的完全进展是必要的，但不是充分的。相反，肿瘤可能会获得进一步过度激活下游 Hh 信号的二次突变，以逃避休眠并进入不受控制的扩张轨迹。
