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

Author:

Huang Xinmei123ORCID,Zhang Shenghua12ORCID,Tang Jingshu12ORCID,Tian Tian45ORCID,Pan Yilin45ORCID,Wu Lina6ORCID,Zhang Jingxuan12ORCID,Liu Yang12ORCID,Huang Jing12ORCID,Dai Hui12ORCID,Xu Weiyan12ORCID,Zhang Youhui7ORCID,Chen Jinfeng8ORCID,Cao Mengshu3ORCID,Zhang Liang459ORCID,Qiu Xiaoyan12ORCID

Affiliation:

1. 1Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.

2. 2NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.

3. 3Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

4. 4Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China.

5. 5City University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, China.

6. 6Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.

7. 7Department of Immunology, Cancer Institute & Hospital, Chinese Academy of Medical Science, Beijing, China.

8. 8Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China.

9. 9Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Futian Research Institute, Shenzhen, Guangdong, China.

Abstract

AbstractElevated 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 mAb 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.Significance:Sialylated cancer IgG activates c-Met-SOX2 signaling to promote stemness properties in cancer cells and can be targeted to suppress tumor growth.

Funder

National Natural Science Foundation of China

Shenzhen Technology Development Program

The Research Grant Council of Hong Kong

Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone Shenzhen Park Project

The Tung Foundation Biomedical Sciences Centre

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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