---
title: "RGS5-positive fibroblast → WNT-like epithelial TGFB axis in colorectal liver metastasis replicated"
id: "biorxiv-0-an-rgs5-positive-fibroblast-to-wnt-like-epithelial-tgfb-axis-in-colorectal"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-an-rgs5-positive-fibroblast-to-wnt-like-epithelial-tgfb-axis-in-colorectal"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1?rss=1"
published_at: "2026-09-10T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# RGS5-positive fibroblast → WNT-like epithelial TGFB axis in colorectal liver metastasis replicated
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-an-rgs5-positive-fibroblast-to-wnt-like-epithelial-tgfb-axis-in-colorectal
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1?rss=1)
- **Published At:** 2026-09-10T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- This preprint reports a reproducible intercellular signalling axis in **colorectal liver metastasis** involving an **RGS5-positive fibroblast** (F2) state and a **WNT-like malignant epithelial** (C2) state driven by **TGFB** signals. - Discovery: single-cell RNA sequencing of paired primary colorectal tumours and liver metastases from six patients identified fibroblast state F2 and epithelial state C2 as enriched in metastases and positioned late in inferred cellular trajectories. - Communication and ligand-target modelling nominated a directional F2-to-C2 programme with transforming growth factor beta as the top-ranked pathway and TGFBR2 enriched in C2 cells. - Spatial transcriptomics of metastatic sections found F2 and C2 occupying the same neighbourhoods in some sections, but spatial co-localisation varied between sections. - Hub genes in the F2→C2 programme included **TPT1**, **SLC1A5**, **SOX4** and **TSC22D1**; protein staining from an independent tissue resource was higher in tumour than normal colon for available proteins. - Replication: an independent paired cohort (five patients plus two metastatic sections) reproduced the same cell states when cell identities were transferred from the discovery data rather than refit; F2 remained enriched in metastases and was the strongest TGFB sender to C2-like epithelium. - Quantitative replication details reported include enrichment metrics for F2 (Ro/E 1.22 versus 0.52; 32% versus 14% of fibroblasts) and for C2-like epithelial cells (1.10 versus 0.86 in metastasis versus primary), and mapping of 92% of the cohort’s MCAM-positive fibroblasts to F2. - The authors emphasise that the directional TGFB axis is a reproducible feature across datasets, but spatial heterogeneity limits strict claims of tight co-localisation of the two states across all sections. - This work used copy-number-based malignant cell identification, trajectory inference, cell-cell communication analyses, ligand-target modelling, spatial transcriptomics, and independent protein staining; all steps were repeated in the validation cohort with fixed cell identity mapping. - The article is a preprint and has not been peer reviewed; competing interests were declared absent by the authors.
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Yingyu Yu 1 Shantou Central Hospital; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Yingyu%2BYu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Yu%20Y&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AYingyu%2BYu%2B) Feifei Ma 2 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Feifei%2BMa%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Ma%20F&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AFeifei%2BMa%2B) Yige Yu 3 The First Affiliated Hospital of Wenzhou Medical University * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Yige%2BYu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Yu%20Y&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AYige%2BYu%2B) * For correspondence: yuyige321@163.com * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5770103/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5770103/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5770103/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5770103/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.06.749652v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5770103/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Background: Colorectal cancer liver metastasis is accompanied by coordinated stromal remodelling, but which fibroblast and malignant epithelial states are coupled, and whether any such coupling holds outside the dataset it was found in, is rarely tested. Methods: Paired primary tumours and liver metastases from six patients were analysed by single-cell RNA sequencing with copy-number-based identification of malignant cells, trajectory inference, cell-cell communication and ligand-target modelling, and spatial transcriptomics of three metastatic sections. Protein staining was taken from an independent tissue resource. Every step was then repeated in a second, independent paired cohort of five patients and two further metastatic sections, with cell identities fixed by transfer from the discovery data rather than refitted. Results: An RGS5-positive fibroblast/pericyte-like state (F2) and a WNT-like malignant epithelial state (C2) were both enriched in metastases and occupied late trajectory positions. Communication analysis nominated a directional F2-to-C2 programme with transforming growth factor beta as the highest-ranked pathway and its receptor TGFBR2 enriched in C2. Spatial data placed the two states in the same neighbourhoods. Hub genes of the programme were TPT1, SLC1A5, SOX4 and TSC22D1, and protein staining was higher in tumour than normal colon for the three with available data. In the independent cohort the same states reappeared: F2 was enriched in metastases (Ro/E 1.22 versus 0.52; 32% versus 14% of fibroblasts), C2-like cells were the most metastasis-enriched epithelial state (1.10 versus 0.86), 92% of the cells that cohort's own authors called MCAM-positive fibroblasts mapped to F2, and F2 was again the strongest TGFB sender to C2-like epithelium at both sites. Conclusions: A directional TGFB axis from an RGS5-positive fibroblast state to a WNT-like epithelial state is a reproducible feature of colorectal liver metastasis rather than a property of one dataset. Its spatial expression varies between sections, which constrains how tightly the two states can be said to be co-localised. ### Competing Interest Statement The authors have declared no competing interest. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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