A Functional Role for Tumor Cell Heterogeneity in a Mouse Model of Small Cell Lung Cancer

SummarySmall cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic RasV12. Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.

► SCLC tumors are often composed of neuroendocrine (NE) and mesenchymal (NonNE) cells
► The NE and NonNE tumor cell lineages are often derived from a common progenitor
► RasV12 can command the transition from the NE to a NonNE phenotype
► NonNE cells endow NE cells with metastatic capacity through paracrine signaling