New publication in Nature Cell Biology

Insights into the cellular origin of cervical metaplasia and cancer.

Epithelial cancers occasionally arise in the transition zones (TZ) between two types of epithelial lineages; these are often preceded by a process called metaplasia, in which the cell types normally present in the tissue are replaced by another cell type. That is the case with cervical cancer that emerges in the TZ between the outer cervix and the inner cervix. The cellular origin of cervical metaplasia remained unclear until now. Here, our single-cell analyses together with stem-cell-derived organoid cell phenotyping and in vivo lineage-tracing outline a meeting point between the stratified squamous cells that cover the ectocervix and the cylindrical columnar cells that cover the endocervix (see figure). Those two distinct epithelial lineages are found to be regulated by opposing stroma-dependent Wnt signals. According to our notion, an imbalance in the signal gradient may cause a shift in cellular differentiation and consequent tissue remodeling. We substantiated this hypothesis in a vitamin A-deficient mouse model of cervical metaplasia: squamous epithelial cells become activated in the endocervix and replace the columnar epithelial cells. Transcription profiles of human cervical cancer samples provide further support for the nature of two distinct epithelia. Ultimately, our findings may help to improve the early diagnosis of cervical cancer.

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Chumduri C, Gurumurthy RK, Berger H, Dietrich O, Kumar N, Koster S, Brinkmann V, Hoffmann K, Drabkina M, Arampatzi P, Son D, Klemm U, Mollenkopf HJ, Herbst H, Mangler M, Vogel J, Saliba AE and Meyer TF. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nature Cell Biology (2021)