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Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma.

Abstract

Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific deletion of Ccn2, associated with reduced expression of alpha-smooth muscle actin and Sox2. Multipotent Sox2-expressing skin-derived precursor (SKP) spheroids were cultured from murine back skin. Using lineage tracing and flow cytometry, approximately 40% of SKPs were found to be derived from a Col1a2 origin and acquired multipotency in culture. Inhibition of mechanotransduction pathways prevented myofibroblast differentiation of SKPs and expression of Ccn2. In SKPs deleted for Ccn2, differentiation into a myofibroblast, but not an adipocyte or neuronal phenotype, was also impaired. In human melanoma, CCN2 expression was associated with a profibrotic ITGA11-expressing subset of cancer-associated fibroblasts that negatively associated with survival. Collectively, these results suggest that synthetic dermal fibroblasts possess a previously unheralded in vivo and in vitro plasticity, and that CCN2 is required for the differentiation of dermal progenitor cells into a myofibroblast/CAF phenotype and is therefore a therapeutic target in melanoma.

Authors+Show Affiliations

Department of Physiology and Pharmacology University of Western Ontario, London, Ontario, Canada.Department of Dentistry University of Western Ontario, London, Ontario, Canada.Department of Oncology University of Alberta, Edmonton, Alberta, Canada; Department of Genetics Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.Department of Physiology and Pharmacology University of Western Ontario, London, Ontario, Canada.Department of Oncology University of Alberta, Edmonton, Alberta, Canada.Department of Physiology and Pharmacology University of Western Ontario, London, Ontario, Canada; Department of Dentistry University of Western Ontario, London, Ontario, Canada. Electronic address: aleask@uwo.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31610176

Citation

Tsang, Matthew, et al. "Insights Into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma." The American Journal of Pathology, 2019.
Tsang M, Quesnel K, Vincent K, et al. Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma. Am J Pathol. 2019.
Tsang, M., Quesnel, K., Vincent, K., Hutchenreuther, J., Postovit, L. M., & Leask, A. (2019). Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma. The American Journal of Pathology, doi:10.1016/j.ajpath.2019.09.006.
Tsang M, et al. Insights Into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma. Am J Pathol. 2019 Oct 11; PubMed PMID: 31610176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma. AU - Tsang,Matthew, AU - Quesnel,Katherine, AU - Vincent,Krista, AU - Hutchenreuther,James, AU - Postovit,Lynne-Marie, AU - Leask,Andrew, Y1 - 2019/10/11/ PY - 2019/02/24/received PY - 2019/08/26/revised PY - 2019/09/03/accepted PY - 2019/10/15/entrez PY - 2019/10/15/pubmed PY - 2019/10/15/medline JF - The American journal of pathology JO - Am. J. Pathol. N2 - Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific deletion of Ccn2, associated with reduced expression of alpha-smooth muscle actin and Sox2. Multipotent Sox2-expressing skin-derived precursor (SKP) spheroids were cultured from murine back skin. Using lineage tracing and flow cytometry, approximately 40% of SKPs were found to be derived from a Col1a2 origin and acquired multipotency in culture. Inhibition of mechanotransduction pathways prevented myofibroblast differentiation of SKPs and expression of Ccn2. In SKPs deleted for Ccn2, differentiation into a myofibroblast, but not an adipocyte or neuronal phenotype, was also impaired. In human melanoma, CCN2 expression was associated with a profibrotic ITGA11-expressing subset of cancer-associated fibroblasts that negatively associated with survival. Collectively, these results suggest that synthetic dermal fibroblasts possess a previously unheralded in vivo and in vitro plasticity, and that CCN2 is required for the differentiation of dermal progenitor cells into a myofibroblast/CAF phenotype and is therefore a therapeutic target in melanoma. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/31610176/Insights_into_Fibroblast_Plasticity:_CCN2_Is_Required_for_Activation_of_Cancer-Associated_Fibroblasts_in_a_Murine_Model_of_Melanoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(19)30754-0 DB - PRIME DP - Unbound Medicine ER -