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Spatial Transcriptomic Landscape of Invasion Patterns in Human Papillomavirus-Associated Endocervical Adenocarcinoma

ABSTRACT: Human papillomavirus (HPV)-associated endocervical adenocarcinoma is the second-most common cancer of the uterine cervix. HPV-associated endocervical adenocarcinoma can be classified into histologic Silva patterns of invasion, which are associated with clinical outcome. However, the mechanisms underlying these patterns of invasion are incompletely understood. We used whole transcriptome spatial transcriptomics to examine gene expression differences separately in the tumor epithelium and the surrounding stromal immune microenvironment (SIME). Seven cases were evaluated, focusing on cases with two distinct patterns of invasion within the same tumor, to control for inter-patient heterogeneity. The most strongly upregulated pathways in both higher-risk tumor epithelium and SIME were associated with extracellular matrix (ECM) remodeling. Transcriptomic-based inference of immune cell populations showed an increase in macrophage populations in higher-risk tumor areas, confirmed by immunohistochemistry. Finally, we derived a four-gene signature from genes upregulated in higher-risk tumor epithelium (KRT6A, TNC, LAMC2 and FN1), which was associated with worse clinical outcome in an independent dataset (The Cancer Genome Atlas). Overall, this work demonstrates that ECM remodeling and macrophage presence are important in the progression to high-risk patterns of invasion in HPV-associated endocervical adenocarcinoma. In addition, we established a prognostic four-gene signature that is predictive of poor outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316098 | GEO | 2026/01/12

REPOSITORIES: GEO

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Project description:Cervical cancer is a common gynecological malignancy, often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study cervical epithelium and the cancers derived thereof. Here, we describe a long-term culturing protocol for ecto- and endocervical epithelia, which generates 3D organoids that stably recapitulate the two tissues of origin. In the example of successful HSV-1 infection, we show that the organoid-based cervical models serve as promising platforms for studying sexually transmitted pathogens. Starting from Pap-brush material, a small biobank of patient-derived tumoroids was established that retained the causative HPV genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutics and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches. Purpose: Transcriptome analysis was performed on organoids/tissues derived from human ecto- and endocervix as well as associated malignancies to characterize the new organoid-based platform. Methods: Ectocervical organoids and tumoroid lines were cultured in M7 media, whereas endocervical organoids in M7+4 media prior harvesting for RNA extraction (see paper for details). Additionally, RNA was extracted from healthy ecto-and endocervical tissue biopsies as well as from primary cells collected via Pap brush method from cervical cancer patients. The libraries were prepared by the Utrecht Sequencing Facility (USEQ) based on polyA enrichment. Sequencing was performed on an Illumina NextSeq500 by using 75-bp single-end or paired-end sequencing. Reads were aligned to the human reference genome (GRCh37) using Burrows-Wheeler Aligner (BWA) (v0.5.9). Viral sequences of different HPV subtypes were detected in the RNA-seq data of the different tumoroid lines and tissues by using VirusSeq-CLI, a wrapper around the VirusSeq pipeline. Results: Ectocervical and endocervical organoids display distinct transcriptomic profiles that can be maintained in cultures for long term. Similarily, the the gene expression profile of tumor organoids clusters apart from healthy counterparts and shows evident tumor-like characteristics. Tumor organoids show expression of causative HPV oncogenes.

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Spatial Transcriptomic Landscape of Invasion Patterns in Human Papillomavirus-Associated Endocervical Adenocarcinoma

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