PP2A Promotes the Symmetric Division of MUC1‐Dominant Cancer Stem‐Like Cells in Small Cell Lung Cancer

Abstract Small cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer. Cancer stem‐like cells (CSLCs) are primarily responsible for carcinogenesis, therapeutic resistance, and tumor recurrence. This study reported that high level of mucin1 (MUC1) is associated with poor patient survival in SCLC. MUC1 expression peaks during the G2/M phase and facilitates symmetric division and expansion of CSLCs. Mechanistically, the interaction of MUC1 and protein phosphatase 2A (PP2A) results in augmented PP2A activity, which leads to reduced phosphorylation of protein kinase C ζ (PKCζ), ultimately decreases phosphorylation of NUMB. Both pharmacological and genetic strategies demonstrate that targeted‐inhibition of the MUC1‐PP2A axis pointedly rescues phosphorylation of PKCζ and NUMB, thereby shifting CSLCs towards asymmetric division and represses CSLCs proliferation. Conversely, inhibitor of PKCζ suppresses phosphorylation of NUMB, promotes symmetric division and induces enrichment of CSLCs. Moreover, combination of etoposide and inhibitors of MUC1‐PP2A pathway efficiently constrains tumor growth in vitro and in vivo. Importantly, a negative correlation is observed between MUC1 and phosphorylation of PKCζ and NUMB in SCLC patients. Therefore, this study reveals a novel mechanism by which MUC1‐PP2A awakes CSLC expansion via switching symmetric division, suggesting a potential therapeutic strategy for MUC1‐positive SCLC.