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

Abstract

Small 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 Ras(V12). 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.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Anton Berns and colleagues studied metastatic potential in a mouse model of small cell lung carcinoma (Calbo et al, 2011). Mesenchymal and neuroendocrine cells derived from a common progenitor, when engrafted into mice as a heterogeneous population triggered metastatic behavior of the neuro-endocrine cells.…”

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…The Seneca Valley virus shows selective tropism for the variant subtype (10). In addition to tumors and cell lines, the variant subtype or its equivalent has been described in GEM models of SCLC (11,12). A summary of the published reports of the variant form and its properties are summarized in Table 1.…”

Tumor heterogeneity-induced signaling regulates SCLC metastasis

“…1 Earlier we have shown that the co-grafting of heterogeneous small cell lung cancer (SCLC) subclones, one growing in suspension with neuroendocrine features (NE cell) and the other clone with adherent mesenchymallike features (NonNE cell) promotes metastasis whereas single clones of either NE or NonNE cells alone only results in local growth. 2 Our data show that tumor heterogeneity can have functional significance resulting in the co-evolution of tumor subclones thereby creating a tumor microenvironment from which NE tumor cells can more effectively metastasize. The inherent genetic instability of tumor subclones might make it easier to select for rare variants that support such crosstalk thereby creating a symbiotic relationship.…”

“…3 Similarly, we have shown that mixed NE and NonNE cell populations gain synergistic proliferation benefits in in vitro cell proliferating assay. 2 This suggests that a close vicinity of NE and NonNE cells promotes rapid tumor growth. However, subcutaneously grafting of mixed populations did not show accelerated local tumor growth as compared to the injection of a single clone population.…”

“…However, subcutaneously grafting of mixed populations did not show accelerated local tumor growth as compared to the injection of a single clone population. 2 This discrepancy might simply be caused by the fact that the subcutaneous microenvironment is more permissive for growth of this tumor. In line with this, we have shown that intravenous grafting of neuroendocrine SCLC clones does result in colonization of liver rather than lung even though many of the tumor cells are initially trapped in lung.…”