Tumor Heterogeneity and Plasticity in Small Cell Lung Cancer

The heterogeneous nature of cell populations in human tumors is a major contributor to tumor evolution, including and perhaps most importantly in response to treatment. Here, we review current knowledge on tumor heterogeneity and cell state plasticity in small cell lung cancer (SCLC), a fast growing and highly metastatic form of lung cancer which develops rapid resistance to therapy. There is a pressing need to expand treatment options for patients with SCLC, which requires a better understanding of the mechanisms by which this disease is able to rapidly grow and evolve in response to therapy. Our current understanding points to epigenetic rather than genetic factors in defining major aspects of inter- and intra-tumoral heterogeneity in SCLC. SCLC is overall considered to be a neuroendocrine (NE) cancer type but SCLC tumors harbor a wide diversity of cancer cell states, including both NE and non-neuroendocrine (non-NE) states, defined by their mutually exclusive expression of a set of transcription factors such as ASCL1, NEUROD1, and POU2F3. The immune microenvironments of SCLC tumors also contain a great deal of heterogeneity. Here, we discuss the different SCLC cell states associated with their defining transcription factors, as well as the epigenetic mechanisms regulating the ability of SCLC cells to switch from one state to another. We further discuss how the composition of SCLC tumors and the surrounding immune cells may affect the response to chemotherapy and immunotherapy. Being able to control plasticity and heterogeneity in SCLC may in the future offer unique opportunities to improve treatment efficacy in this recalcitrant cancer.