Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia
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PROVIDER: PRJNA529644 | ENA |
REPOSITORIES: ENA
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Project description:The transition zones (TZs) of the squamous and columnar epithelium constitute hotspots for the emergence of cancers, often preceded by metaplasia, where one epithelial type is replaced by cells of another type. Yet, it remains uncertain how the spatial organization of the epithelia is maintained and how the TZ niche is remodeled during metaplasia. Here, we used single-cell RNA-sequencing to characterize subpopulations of the epithelium as well as the underlying stromal compartment of endo and ectocervix, encompassing the TZ. Mouse lineage tracing, organoid culture and smRNA-ISH revealed that the two epithelia derive from two separate cervix-resident lineage-specific stem cell populations that are regulated by opposing WNT signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodeling and increased expression of WNT signaling inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Thus, homeostasis at the TZ results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.
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Project description:The cellular origin of cervical cancers remains unclear. Revealing molecular details of transformation in this tissue has been hampered by the lack of culture systems, resembling the in vivo cervical architecture. Here we established a long-term in vitro 3D cervical organoid model derived from stem cells of human or mouse cervical tissue which recapitulates the in vivo stratified ectocervical and columnar endocervical epithelium. Stratified and columnar cervical epithelia arise from two discrete unipotent stem cell populations of the endocervix. Unique stem cell signatures reveal a dependency on intrinsic Notch and Wnt microenvironmental signals. The genetic signatures of KRT5+ stratified vs KRT7+ columnar cervical cells establish discrete groups of cervical cancer of the squamous and adenocarcinoma types, respectively. Cervical tissue morphology is guided by the interplay of two discrete unipotent cervical stem cell populations and the spatio-temporal distribution of signals from the stroma.
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