A Self-Propagating c-Met–SOX2 Axis Drives Cancer-Derived IgG Signaling That Promotes Lung Cancer Cell Stemness

Abstract

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.

The prognostic value of sialylation-related long non-coding RNAs in lung adenocarcinoma

“…Previous studies have reported the overexpression of SOX2 promotes the accumulation of ST6Gal-I glycosyltransferase, imparting cancer stem cell characteristics in ovarian and pancreatic cancer cells 26 . Additionally, abnormal activation of the c-Met-SOX2 axis, mediated by sialylated IgG, enhances the stemness of lung cancer cells 27 . The co-regulation of LINC00857, LINC00968, LINC00663, and ITGA9-AS1 on SOX2 suggested their potential contributions in aberrant sialylation process during tumor progression.…”

“…Notably, we observed their interactions with three genes, namely IGF2BP3, SOX2, and IGFBP1. Although the potential regulatory mechanisms of IGF2BP3 and IGF2BP1 require further exploration, it has been shown that SOX2 regulates the stemness of cancer cells by mediating sialylation processes, emphasizing the significance of the four lncRNAs in sialylation and tumor progression 26 , 27 .…”

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer

“…To break through the conventional therapeutic resistance, CSC-based therapy strategies have been widely investigated. , CSC-targeted strategies include targeting major transcription factors ( i.e. , Nanog, Sox2, Oct4, FOXM1), which are essential for the maintenance of the pluripotency of CSCs and regulated by miRNAs, and targeting CSC-related signal pathways. − Many endogenous or exogenous genes and microRNAs regulate these complex pathways, including Wnt, Hedgehog, NF-κB (nuclear factor-κB), Notch, JAK-STAT (Janus kinase/signal transducers and activators of transcription), and PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin). , Small molecule inhibitors of signaling pathway components in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, ivosidenib, and venetoclax, have been approved by the FDA. , Vismodegib, a hedgehog inhibitor, can bind to smoothened (SMO) and lead to inhibition of an aberrant activation of the hedgehog pathway. , Moreover, vismodegib targets at least a subset of CSCs in basal-cell carcinoma and head and neck squamous cells, indicating that regulating CSCs is a promising way to improve the therapeutic effect of ESCC. , Compared with small-molecule inhibitors and their precise chemical structure, miRNA is easier to develop as an attractive approach for the treatment of cancer. , Several miRNA-based formulations, including the locked nucleic-acid–based miR-122 antagonist and liposomal miR-34 mimic, have entered phase I or II clinical trials, indicating the promise of gene therapy . Most importantly, miRNAs can regulate the gain or maintenance of CSC features and are considered promising therapeutic targets to restrain the therapeutic resistance of CSCs.…”