Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

Cindrilla Chumduri; Rajendra Kumar Gurumurthy; Hilmar   Berger; Oliver  Dietrich; Naveen Kumar; Stefanie  Koster; Volker Brinkmann; Kirstin   Hoffmann; Marina   Drabkina; Panagiota  Arampatzi; Dajung  Son; Uwe  Klemm; Hans-Joachim Mollenkopf; Hermann  Herbst; Mandy  Mangler; Jörg  Vogel; Antoine-Emmanuel   Saliba; Thomas F Meyer

doi:10.1038/s41556-020-00619-0

Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

Cindrilla Chumduri^*, Rajendra Kumar Gurumurthy, Hilmar Berger, Oliver Dietrich, Naveen Kumar, Stefanie Koster, Volker Brinkmann, Kirstin Hoffmann, Marina Drabkina, Panagiota Arampatzi, Dajung Son, Uwe Klemm, Hans-Joachim Mollenkopf, Hermann Herbst, Mandy Mangler, Jörg Vogel, Antoine-Emmanuel Saliba, Thomas F Meyer^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Nature Cell Biology
Volume	23
Pages (from-to)	184–197
Number of pages	14
ISSN	1465-7392
DOIs	https://doi.org/10.1038/s41556-020-00619-0
Publication status	Published - 18 Jan 2021
Externally published	Yes

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Chumduri, C., Kumar Gurumurthy, R., Berger, H., Dietrich, O., Kumar, N., Koster, S., Brinkmann, V., Hoffmann, K., Drabkina, M., Arampatzi, P., Son, D., Klemm, U., Mollenkopf, H.-J., Herbst, H., Mangler, M., Vogel, J., Saliba, A.-E., & Meyer, T. F. (2021). Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nature Cell Biology, 23, 184–197. https://doi.org/10.1038/s41556-020-00619-0

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title = "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.",

author = "Cindrilla Chumduri and {Kumar Gurumurthy}, Rajendra and Hilmar Berger and Oliver Dietrich and Naveen Kumar and Stefanie Koster and Volker Brinkmann and Kirstin Hoffmann and Marina Drabkina and Panagiota Arampatzi and Dajung Son and Uwe Klemm and Hans-Joachim Mollenkopf and Hermann Herbst and Mandy Mangler and J{\"o}rg Vogel and Antoine-Emmanuel Saliba and Meyer, {Thomas F}",

year = "2021",

month = jan,

day = "18",

doi = "10.1038/s41556-020-00619-0",

language = "English",

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pages = "184–197",

journal = "Nature Cell Biology",

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Chumduri, C, Kumar Gurumurthy, R, Berger, H, Dietrich, O, Kumar, N, Koster, S, Brinkmann, V, Hoffmann, K, Drabkina, M, Arampatzi, P, Son, D, Klemm, U, Mollenkopf, H-J, Herbst, H, Mangler, M, Vogel, J, Saliba, A-E & Meyer, TF 2021, 'Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia', Nature Cell Biology, vol. 23, pp. 184–197. https://doi.org/10.1038/s41556-020-00619-0

Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. / Chumduri, Cindrilla; Kumar Gurumurthy, Rajendra; Berger, Hilmar et al.
In: Nature Cell Biology, Vol. 23, 18.01.2021, p. 184–197.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

AU - Chumduri, Cindrilla

AU - Kumar Gurumurthy, Rajendra

AU - Berger, Hilmar

AU - Dietrich, Oliver

AU - Kumar, Naveen

AU - Koster, Stefanie

AU - Brinkmann, Volker

AU - Hoffmann, Kirstin

AU - Drabkina, Marina

AU - Arampatzi, Panagiota

AU - Son, Dajung

AU - Klemm, Uwe

AU - Mollenkopf, Hans-Joachim

AU - Herbst, Hermann

AU - Mangler, Mandy

AU - Vogel, Jörg

AU - Saliba, Antoine-Emmanuel

AU - Meyer, Thomas F

PY - 2021/1/18

Y1 - 2021/1/18

N2 - 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.

AB - 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.

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U2 - 10.1038/s41556-020-00619-0

DO - 10.1038/s41556-020-00619-0

M3 - Journal article

SN - 1465-7392

VL - 23

SP - 184

EP - 197

JO - Nature Cell Biology

JF - Nature Cell Biology

ER -

Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

Abstract

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