Decipher heterogeneity of cervical squamous cell carcinoma and adenocarcinoma with different HPV status: combining scRNA and TCR-seq with 3D organoid

Although adenocarcinoma of the cervix (ADC) exhibits a more malignant phenotype and poorer prognosis than squamous cell carcinoma (SCC), they are treated identically. This clinical dilemma calls for deeper investigation into differences between SCC and ADC. We studied 3 human papillomavirus (HPV)-positive SCC, 3 HPV-associated (HPVA) and 2 non-HPV-associated (NHPVA) ADC samples with single-cell RNA and T cell receptor sequencing plus 3D organoid verification. Notably, we revealed the malignant origin of epithelial cells characterized by stemness and poor differentiation and the potential mechanism of HPVA and NHPVA oncogenesis, deciphering differences between SCC and ADC. Additionally, we discovered the key role of tip cells in sprouting angiogenesis, the protumoral effects of cancer-associated fibroblasts and the functional dysregulation of T lymphocytes. We highlighted tumor microenvironment differences between different histologic subtypes through cellular interaction analysis. Importantly, we discovered novel precise treatment strategies specifically for HPV-positive SCC, HPVA and NHPVA-ADC, providing tremendous clinical value. Overall design: We performed scRNA-seq and TCR-seq of 8 cervical cancer samples including 3 HPV-positive SCC samples, 3 HPVA ADC samples and 2NHPVA ADC samples