Dynamic Reprogramming of Stromal Pdgfra-expressing Cells During WNT-Mediated Transformation of the Intestinal Epithelium

Overview

Journal bioRxiv

Date 2025 Feb 3

PMID 39896606

Authors

O Pellon-Cardenas

P Rout

S Hassan

E Fokas

He Ping

I Patel

J Patel

O Plotsker

A Wu

R Kumar

M Akther

A Logerfo

S Wu

D E Wagner

D Boffelli

K D Walton

E Manieri

K Tong

J R Spence

N J Bessman

R A Shivdasani

M P Verzi

Affiliations

Soon will be listed here.

Abstract

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis and provide a niche that supports adjacent epithelial stem cells. Here we report that -expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids . Genetic reduction of in the β-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue . These results demonstrate that Pdgfra fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.

References

Tape C . Plastic persisters: revival stem cells in colorectal cancer. Trends Cancer. 2023; 10(3):185-195. DOI: 10.1016/j.trecan.2023.11.003. View

Verzi M, Shin H, He H, Sulahian R, Meyer C, Montgomery R . Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev Cell. 2010; 19(5):713-26. PMC: 3001591. DOI: 10.1016/j.devcel.2010.10.006. View

Goto N, Westcott P, Goto S, Imada S, Taylor M, Eng G . SOX17 enables immune evasion of early colorectal adenomas and cancers. Nature. 2024; 627(8004):636-645. DOI: 10.1038/s41586-024-07135-3. View

Ayyaz A, Kumar S, Sangiorgi B, Ghoshal B, Gosio J, Ouladan S . Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature. 2019; 569(7754):121-125. DOI: 10.1038/s41586-019-1154-y. View

Sato T, Stange D, Ferrante M, Vries R, van Es J, van den Brink S . Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology. 2011; 141(5):1762-72. DOI: 10.1053/j.gastro.2011.07.050. View

Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C . Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med. 2014; 21(1):62-70. PMC: 4594755. DOI: 10.1038/nm.3750. View

Wolf F, Angerer P, Theis F . SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 2018; 19(1):15. PMC: 5802054. DOI: 10.1186/s13059-017-1382-0. View

Tsukui T, Wolters P, Sheppard D . Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature. 2024; 631(8021):627-634. DOI: 10.1038/s41586-024-07660-1. View

Barker N, van Es J, Kuipers J, Kujala P, van den Born M, Cozijnsen M . Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007; 449(7165):1003-7. DOI: 10.1038/nature06196. View

10.

Theodosiou N, Tabin C . Wnt signaling during development of the gastrointestinal tract. Dev Biol. 2003; 259(2):258-71. DOI: 10.1016/s0012-1606(03)00185-4. View

11.

Kabiri Z, Greicius G, Madan B, Biechele S, Zhong Z, Zaribafzadeh H . Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. 2014; 141(11):2206-15. DOI: 10.1242/dev.104976. View

12.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C . The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11):1350-6. PMC: 4636487. DOI: 10.1038/nm.3967. View

13.

Mustata R, Vasile G, Fernandez-Vallone V, Strollo S, Lefort A, Libert F . Identification of Lgr5-independent spheroid-generating progenitors of the mouse fetal intestinal epithelium. Cell Rep. 2013; 5(2):421-32. DOI: 10.1016/j.celrep.2013.09.005. View

14.

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View

15.

Degirmenci B, Valenta T, Dimitrieva S, Hausmann G, Basler K . GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature. 2018; 558(7710):449-453. DOI: 10.1038/s41586-018-0190-3. View

16.

Harris R, Chung E, Coffey R . EGF receptor ligands. Exp Cell Res. 2003; 284(1):2-13. DOI: 10.1016/s0014-4827(02)00105-2. View

17.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

18.

Abudukelimu S, de Miranda N, Hawinkels L . Fibroblasts in Orchestrating Colorectal Tumorigenesis and Progression. Cell Mol Gastroenterol Hepatol. 2024; 17(5):821-826. PMC: 10966773. DOI: 10.1016/j.jcmgh.2024.01.013. View

19.

Huels D, Ridgway R, Radulescu S, Leushacke M, Campbell A, Biswas S . E-cadherin can limit the transforming properties of activating β-catenin mutations. EMBO J. 2015; 34(18):2321-33. PMC: 4570519. DOI: 10.15252/embj.201591739. View

20.

McCarthy N, Manieri E, Storm E, Saadatpour A, Luoma A, Kapoor V . Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient. Cell Stem Cell. 2020; 26(3):391-402.e5. PMC: 7412576. DOI: 10.1016/j.stem.2020.01.008. View