N-MYC amplification as a secondary mutation that promotes basal cell carcinoma progression

Summary: Abstract Body: Basal cell carcinoma (BCC) is by far the world’s most common cancer. Although these tumors are initiated by mutations that activate upstream Hedgehog signaling—loss of PTCH1 or constitutive activation of SMO—our previous studies have revealed that secondary mutations are also required to drive subsequent tumor progression from microscopic to macroscopic disease. MYCN is recurrently amplified or stabilized in human BCC, and N-Myc is upregulated in mouse BCCs. Here, we show that genetic deletion of Mycn delays tumor progression in a BCC mouse model initiated by loss of Ptch1. Using a newly developed in vitro system for culturing numerous mouse BCC cell lines, we further observed that Hedgehog signaling is rapidly silenced in vitro, and that inducible expression of N-MYC promotes tumor cell expansion by downregulating differentiation markers such as Keratin 10 and Notch pathway activation. Critically, N-MYC overexpression in vivo also downregulates Keratin 10 and Notch signaling in tumors. Finally, RNA-seq and functional analyses suggest that N-MYC can modulate components of the TGFb superfamily. Altogether, our work identifies both N-MYC-dependent and –independent mechanisms that drive BCC progression to malignant disease. Shih-Ying Tsai¹, Thomas Huyge¹, Marina Grachtchouk¹, Andrzej A. Dlugosz¹, Sunny Wong¹ 1. Dermatology, University of Michigan, Ann Arbor, MI, United States. UV Biology/Injury and Non-melanoma Cancers