Small-sized colorectal cancer cells harbor metastatic tumor-initiating cells

Colorectal cancer (CRC) is heterogeneous and contains different-sized cells. Recent studies have shown that tumor-initiating cells (TICs) are involved in cancer initiation, recurrence and metastasis. However, connections between cancer cell size and stem-like properties are largely unknown. Here we purified large- and small-sized CRC cells by fluorescence-activated cell sorting (FACS) based on forward scatter (FSC), and demonstrated that small CRC cells possess higher holoclone- and sphere-forming capacity in vitro, tumor-initiating capacity in vivo and form more lung metastases compared with large CRC cells. Furthermore, we found that down-regulated YAP1 (yes-associated protein 1) decreased tumor-initiating and metastatic capacity in small CRC cells but not in large CRC cells. More importantly, our results showed that the expression of YAP1 positively correlated with the poor prognosis in CRCs. Collectively, our findings suggest that small CRC cells enrich for metastatic TICs, and YAP1 is one of the potential therapeutic targets of metastatic TICs, the small CRC cells.