Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer

• CD24High CD44Low EpCAMHigh mark tumor-propagating cells (TPCs) in mouse SCLC
• SCLC TPCs generate non-TPCs and are proliferative and abundant but not chemoresistant
• Elevated MYC activity is required for the maintenance of TPCs in SCLC tumors
• A low dose of the transcriptional inhibitor JQ1 inhibits long-term SCLC growth

SummarySmall cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.

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