Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer.



Hanley, Christopher Jon, Waise, Sara, Rachel, Parker, Lopez, Maria-Antoinette, Taylor, Julian, Kimbley, Lucy, West, Jonathon, Ottensmeier, Christian ORCID: 0000-0003-3619-1657, Rose-Zerilli, Mat and Thomas, Gareth
(2020) Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer. CANCER RESEARCH, 80 (21).

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Abstract

Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumour progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. This identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-β1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-β1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo phenotypes. Similarly, IL-1β treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signalling identified additional pathways and cell interactions likely to be involved in fibroblast activation, which can be examined using publicly available R shiny applications (at the following links: myofibroblast activation and inflammatory fibroblast activation ). This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC.

Item Type: Article
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 Apr 2023 09:21
Last Modified: 19 Apr 2023 09:21
DOI: 10.1101/2020.06.08.134270
Open Access URL: https://www.biorxiv.org/content/10.1101/2020.06.08...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3169678