title: A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers.
abstract: Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hanley
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Fergus
authors.initials: F
authors.lastname: Noble
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ward
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Bullock
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin 53706, USA.
authors.forename: Cole
authors.initials: C
authors.lastname: Drifka
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Manousopoulou
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Johnston
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Hayden
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Thirdborough
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin 53706, USA.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Mellows
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin 53706, USA.
authors.forename: W John
authors.initials: WJ
authors.lastname: Kao
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.|Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Spiros D
authors.initials: SD
authors.lastname: Garbis
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Mirnezami
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Underwood
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin 53706, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D058628:Myofibroblasts / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D059016:Tumor Microenvironment
chemical_list: D003094:Collagen
keywords: cancer associated fibroblasts; collagen; extracellular matrix; second harmonic generation; tumor microenvironment