A self-propagating c-Met-SOX2 axis drives cancer-derived IgG signaling that promotes lung cancer cell stemness.
Cancer research(2023)
摘要
Elevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the monoclonal antibody RP215, which specifically recognizes the Asn162 sialylation-related epitope on SIA-cIgG, effectively blocked the SIA-cIgG-driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.
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关键词
lung cancer-derived,signaling,igg,self-propagating,c-met
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