Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ

Uppsala universitet, Experimentell och klinisk onkologi Uppsala universitet, Science for Life Laboratory, SciLifeLab Uppsala universitet, Molekylära verktyg Uppsala universitet, Endokrinkirurgi Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden Mayo Clin, Comprehens Canc Ctr, Dept Canc Biol, Jacksonville, FL 32224 USA Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Karolinska Univ Hosp, Radiumhemmet, Stockholm, Sweden Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden 2019

Background: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Methods: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. Results: PDGFR alpha((low))/PDGFR beta((high)) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. Conclusions: A PDGFR alpha((low))/PDGFR beta((high)) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights ep

Cancer and Oncology; Cancer och onkologi; Cell and Molecular Biology; Cell- och molekylärbiologi; Article in journal; info:eu-repo/semantics/article; text

10.1093.jnci.djy234

Open access content. Open access content
info:eu-repo/semantics/restrictedAccess

English

UPE oai:DiVA.org:uu-397124
0000-0002-4394-2634
doi:10.1093/jnci/djy234
PMID 30816935
ISI:000493067400014
1235235235

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