Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

Neoplasia : an International Journal for Oncology Research
Anisha M HammerMichael C Ostrowski

Abstract

The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA) and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary...Continue Reading

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Citations

Oct 16, 2018·Journal of Cellular Biochemistry·Masoud NajafiKeywan Mortezaee
Jun 6, 2018·Frontiers in Cell and Developmental Biology·James B McCarthyEva A Turley
Jan 17, 2020·Advanced Healthcare Materials·Chia-Wen ChangJonathan W Song
Feb 15, 2019·Frontiers in Bioengineering and Biotechnology·Alex AvendanoJonathan W Song
May 1, 2019·Biology Open·Sudipa June ChatterjeeLuke McCaffrey
Apr 1, 2021·Cell Reports·Jingqiang WangYi Arial Zeng
Apr 10, 2021·Journal of Mammary Gland Biology and Neoplasia·Caleb A Dawson, Jane E Visvader
Nov 8, 2020·Seminars in Cell & Developmental Biology·Jakub SumbalZuzana Koledova
Jul 23, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Arian Ansardamavandi, Mohammad Tafazzoli-Shadpour
Apr 16, 2020·ACS Biomaterials Science & Engineering·Alex AvendanoJonathan W Song

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Methods Mentioned

BETA
genetic modifications
atomic force microscopy
AFM
PCR
X-ray
force measurements
PCRs
genotyping

Software Mentioned

MATLAB
JMP
ImageJ
Comsol

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