Small-cell lung cancer (SCLC) is characterized by mutation of the p53 and Rb tumor suppressors, and patients face a dismal prognosis with few treatment options. SCLC can be classified into four subtypes based on the expression of certain key genetic regulators, such as ASCL1 and NEUROD1, but how these subtypes are established despite common driver events remains to be defined. Here, Voigt, Wallenburg, and colleagues show that upregulation of the pluripotency factor SOX2 following Rb loss of function is a key determinant of SCLC phenotypic diversity. Using a conditional Sox2 knockout mouse model, the authors demonstrate that SOX2 upregulation is critical for initiation of tumors from pulmonary neuroendocrine cells. Transcriptomic analysis revealed that SOX2 regulated the expression of a broad network of stemness factors, including NEUROD1 and MYC family members. These data indicate that SOX2 may be involved in regulating SCLC tumorigenesis, as well as progression from the ASCL1 subtyp....

You do not currently have access to this content.