02199nas a2200325   4500000000100000008004100001260001500042100001600057700001800073700001400091700001200105700001500117700001000132700001400142700001300156700001600169700001600185700001700201700001400218700001800232700001400250700001500264700001600279700001200295245011900307856005500426300001300481490000700494520137200501       2024                            d  c2024-05-151 aHaonan Song1 aHaoyuan Jiang1 aWeichu Hu1 aYan Hai1 aYihuan Cai1 aHu Li1 aYuru Liao1 aYi Huang1 aXiaogang Lv1 aYefei Zhang1 aJiping Zhang1 aYan Huang1 aXiaomei Liang1 aHao Huang1 aXinhua Lin1 aYifeng Wang1 aXiao Yi00aCervical extracellular matrix hydrogel optimizes tumor heterogeneity of cervical squamous cell carcinoma organoids  uhttps://www.science.org/doi/10.1126/sciadv.adl3511  aeadl35110 v103 aCervical 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.