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

Carina Strell, Janna Paulsson, Shao-Bo Jin, Nicholas P Tobin, Artur Mezheyeuski, Pernilla Roswall, Ceren Mutgan, Nicholas Mitsios, Hemming Johansson, Sarah Marie Wickberg, Jessica Svedlund, Mats Nilsson, Per Hall, Jan Mulder, Derek C Radisky, Kristian Pietras, Jonas Bergh, Urban Lendahl, Fredrik Wärnberg, Arne Östman

Research output: Contribution to journalArticlepeer-review

Abstract

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: PDGFRα(low)/PDGFRβ(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 PDGFRα(low)/PDGFRβ(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 epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.

Original languageEnglish
Pages (from-to)983-995
JournalJournal of the National Cancer Institute
Volume111
Issue number9
Early online date2019 Feb 28
DOIs
Publication statusPublished - 2019

Subject classification (UKÄ)

  • Cancer and Oncology
  • Cell and Molecular Biology

Fingerprint

Dive into the research topics of 'Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ'. Together they form a unique fingerprint.

Cite this