Tumor-resident stromal cells promote breast cancer Invasion through regulation of the basal phenotype
Tumor-resident stromal cells promote breast cancer Invasion through regulation of the basal phenotype
Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal-mediated extracellular matrix (ECM) organization module. We then developed a novel coculture model of tumor organoids with autologous stromal cells. Coculture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGFβ and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGFβ induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel coculture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior. Implications: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/11/1615/F1.large.jpg.
1615–1622
Hanley, Christopher
7e2d840d-e724-4389-a362-83741ccdf241
Henriet, Elodie
e1222c2d-c296-4801-90da-699f523785ac
Sirka, Orit Katarina
3c22bd63-764d-45f7-86ce-56a8cf2d429c
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Ewald, Andrew
f4b81689-49cd-4752-86b7-8e269d6d1c83
3 November 2020
Hanley, Christopher
7e2d840d-e724-4389-a362-83741ccdf241
Henriet, Elodie
e1222c2d-c296-4801-90da-699f523785ac
Sirka, Orit Katarina
3c22bd63-764d-45f7-86ce-56a8cf2d429c
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Ewald, Andrew
f4b81689-49cd-4752-86b7-8e269d6d1c83
Hanley, Christopher, Henriet, Elodie, Sirka, Orit Katarina, Thomas, Gareth and Ewald, Andrew
(2020)
Tumor-resident stromal cells promote breast cancer Invasion through regulation of the basal phenotype.
Molecular cancer research : MCR, 18 (11), .
(doi:10.1158/1541-7786.mcr-20-0334).
Abstract
Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal-mediated extracellular matrix (ECM) organization module. We then developed a novel coculture model of tumor organoids with autologous stromal cells. Coculture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGFβ and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGFβ induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel coculture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior. Implications: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/11/1615/F1.large.jpg.
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More information
Accepted/In Press date: 11 August 2020
Published date: 3 November 2020
Additional Information:
C.J. Hanley reports grants from CRUK during the conduct of the study; in addition, C.J. Hanley has a patent for WO2019086579, use of Nox inhibitors for treatment of cancer (named coinventor) issued, and the NOX1/4 inhibitior (GKT831) was kindly donated by Genkyotex. G.J. Thomas reports nonfinancial support from Genkyotex (supplied NOX1/4 inhibitor GKT137831) during the conduct of the study, in addition, G.J. Thomas has a patent for WO201908657, use of NOX inhibitors for the treatment of cancer issued (coinventor). A.J. Ewald reports grants from NIH/NCI, BCRF/Pink Agenda, and Commonwealth Foundation during the conduct of the study and other from ImmunoCore (spouse is employee), and MedImmune (spouse was formerly an employee), outside the submitted work; in addition, A.J. Ewald has a patent for molecular signatures of invasive cancer subpopulations (US 10545133) issued. No potential conflicts of interest were disclosed by the other authors.
Identifiers
Local EPrints ID: 470750
URI: http://eprints.soton.ac.uk/id/eprint/470750
PURE UUID: f0c2424b-014e-4e46-8ca3-5171fd9910d7
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Date deposited: 19 Oct 2022 16:50
Last modified: 17 Mar 2024 03:37
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Contributors
Author:
Elodie Henriet
Author:
Orit Katarina Sirka
Author:
Andrew Ewald
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