Small cell lung cancer (SCLC) is a highly aggressive, particularly deadly form of cancer noted for its early metastasis and resistance to therapy. One explanation for these traits is that SCLC is usually composed of heterogeneous cell populations, most often including cells with neuroendocrine (NE) traits and those with mesenchymal-like (ML) traits. These distinct populations are not associated with specific genetic mutations as are frequently seen in other forms of cancer, and their origin is not fully understood. Now, however, Vanderbilt Basic Sciences researchers Vito Quaranta and Jonathan Irish and their laboratories report the results of gene expression studies using data from 53 SCLC cell lines and 28 patient tumors. Their results confirmed that most tumors and cell lines comprised two major cell types, NE and ML, and they were able to identify a set of 33 transcription factors that were differentially activated in the two primary phenotypes. Careful examination of each of the cell lines and tumors revealed, however, that not all of them fit into the NE or ML classification. Single cell flow cytometry of these samples demonstrated that the cells were a hybrid between the NE and ML phenotypes. Further studies showed that treatment of SCLC with standard forms of chemotherapy resulted in a shift of the cells towards a hybrid phenotype. The researchers concluded that the heterogeneity observed in SCLC is the result of the level of activation or inactivation of 33 key transcription factors and that changes in the activity of those factors in response to stress, including therapy, can lead to adaptations that result in cell survival and drug resistance. These insights will be valuable in designing new approaches to SCLC treatment in the future. The work is published in the journal Cancer Research [A. R. Udyavar, et al. (2016) Cancer Res., published online December 8, DOI: 10.1158/0008-5472.CAN-16-1467].