Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

Abstract

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.

Organoids of the Female Reproductive Tract: Innovative Tools to Study Desired to Unwelcome Processes

“…The organoid cells expressed validated SCJ markers more robustly than classic cell lines and displayed both differentiated endo-and ectocervical cell types. Chumduri et al (2018Chumduri et al ( , 2021) generated endocervical-like, longterm expandable organoids from ecto-and endocervical patient samples, dependent on the presence of Wnt agonists (RSPO1 and WNT3A). They showed differentiation potential toward an ectocervical phenotype by activating the cAMP pathway and hinted toward different originating cells (i.e., squamous cancers from CK7 + and adenocarcinomas from CK7 + CK8 + cells).…”

Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies

“…Furthermore, organoids established from human and mouse ecto-and endo-cervical cells revealed that the two epithelial cell types descend from distinct cervical lineage-specific stem cell populations which are regulated by divergent stromal Wnt signals. PDOs from human ecto-and endo-cervical lineages faithfully recapitulated the in vivo architecture and could be maintained in culture for more than six months [12]. Radiation therapy is a mainstay therapy for cervical cancer patients, and the radiosensitivity of cervical cancers is quite diverse.…”

“…The intersection between intrinsic and extrinsic factors in tumour development occurs at the level of the stem-cell compartment, which is regulated by paracrine signalling. A recent study in mice demonstrated that the Wnt gradient defines the border between endocervical columnar epithelium and squamous epithelium of the ectocervix, where likely two different populations of stem cells are regenerating epithelial compartments depending on the signalling received from the stroma [12]. While expression of Krt5/Krt14 markers characterize squamous epithelium, columnar lineage exhibits hallmark expression of Krt8/Krt19.…”

Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment

“…The mucosal epithelium of different organs often exposed to extrinsic factors like diet, toxins, and microbes are predisposed to carcinogenesis. Epithelial transition zones where two different epithelial types meet represent hotspots of preneoplastic metaplasia, altered microbiota and cancer development [1][2][3][4] . Gastroesophageal junction (GEJ) is one of those transition zones defined by the Z-line where the mucosa of the distal esophagus and the proximal stomach meet.…”