Cervical extracellular matrix hydrogel optimizes tumor heterogeneity of cervical squamous cell carcinoma organoids

Author:

Song Haonan1ORCID,Jiang Haoyuan1ORCID,Hu Weichu1ORCID,Hai Yan1ORCID,Cai Yihuan1ORCID,Li Hu2,Liao Yuru1,Huang Yi3,Lv Xiaogang4,Zhang Yefei1,Zhang Jiping5,Huang Yan6,Liang Xiaomei1ORCID,Huang Hao3ORCID,Lin Xinhua78ORCID,Wang Yifeng1ORCID,Yi Xiao17ORCID

Affiliation:

1. Department of Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.

2. The First Affiliated Hospital, Jinan University, Guangzhou 510280, China.

3. Department of Gynecology, The Sixth Affiliated Hospital, South China University of Technology, Foshan 528200, China.

4. Department of Gynecologic Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510030, China.

5. Department of Gynecology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, China.

6. Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.

7. Greater Bay Area Institute of Precision Medicine, Guangzhou 510280, China.

8. State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University Shanghai, Shanghai 200438, China.

Abstract

Cervical cancer, primarily squamous cell carcinoma, is the most prevalent gynecologic malignancy. Organoids can mimic tumor development in vitro, but current Matrigel inaccurately replicates the tissue-specific microenvironment. This limitation compromises the accurate representation of tumor heterogeneity. We collected para-cancerous cervical tissues from patients diagnosed with cervical squamous cell carcinoma (CSCC) and prepared uterine cervix extracellular matrix (UCEM) hydrogels. Proteomic analysis of UCEM identified several tissue-specific signaling pathways including human papillomavirus, phosphatidylinositol 3-kinase–AKT, and extracellular matrix receptor. Secreted proteins like FLNA, MYH9, HSPA8, and EEF1A1 were present, indicating UCEM successfully maintained cervical proteins. UCEM provided a tailored microenvironment for CSCC organoids, enabling formation and growth while preserving tumorigenic potential. RNA sequencing showed UCEM-organoids exhibited greater similarity to native CSCC and reflected tumor heterogeneity by exhibiting CSCC-associated signaling pathways including virus protein-cytokine, nuclear factor κB, tumor necrosis factor, and oncogenes EGR1, FPR1, and IFI6. Moreover, UCEM-organoids developed chemotherapy resistance. Our research provides insights into advanced organoid technology through native matrix hydrogels.

Publisher

American Association for the Advancement of Science (AAAS)

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