Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium
Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt-villus axis in the intestine and provide a niche that supports intestinal stem cells. Here, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations 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 TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation.
Authors
- Jay Patel (ORCID: https://orcid.org/0000-0002-8507-795X)
- Nicholas J. Bessman (ORCID: https://orcid.org/0000-0002-6645-0990)
- Oscar Pellón-Cárdenas (ORCID: https://orcid.org/0000-0003-3085-1618)
- Kevin Tong (ORCID: https://orcid.org/0009-0002-6371-4644)
- Elisa Manieri (ORCID: https://orcid.org/0000-0003-3150-7528)
- Jahangir Iqbal (ORCID: https://orcid.org/0000-0002-9021-2271)
- Michael P. Verzi (ORCID: https://orcid.org/0000-0003-4082-4330)
- Lukui Chen (ORCID: https://orcid.org/0000-0002-8075-8369)
- Xia Qiu
- Siwen Wu (ORCID: https://orcid.org/0000-0003-2393-4650)
- Sohaib Hassan (ORCID: https://orcid.org/0000-0002-1313-0387)
- Ramesh A. Shivdasani (ORCID: https://orcid.org/0000-0002-2828-1727)
- Alex Wu
- Alexandra Logerfo (ORCID: https://orcid.org/0000-0002-1853-695X)
- Emily E. Fokas (ORCID: https://orcid.org/0000-0002-6041-8682)
- Olivia N. Nussbaum
- Rohit Kumar (ORCID: https://orcid.org/0000-0003-1173-7369)
- Ping He (ORCID: https://orcid.org/0000-0003-0125-7441)
- Katherine D. Walton (ORCID: https://orcid.org/0000-0001-9108-5617)
- Prateeksha Rout
- Masuda Akther
- Jason R. Spence
- Isha Patel
- Dario Boffelli
- Daniel Wagner
- Ruoxuan Xiao
Institutions
- Rutgers, The State University of New Jersey (US)
- Cedars-Sinai Medical Center (US)
- Hackensack University Medical Center (US)
- University of Veterinary Medicine Vienna (AT)
- University of California, San Francisco (US)
- University of Michigan (US)
- Southeast University (BD)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- Michigan Medicine (US)
- Dana-Farber Cancer Institute (US)
- Ann Arbor Center for Independent Living (US)
- Southeast University (CN)
- University of San Francisco (US)
- Stanford University (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-03-05
- DOI
- https://doi.org/10.1158/0008-5472.can-25-0101
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00