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Uncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform

Author

Listed:
  • Matthew L. Kutys

    (Boston University
    Harvard University
    University of California San Francisco)

  • William J. Polacheck

    (Boston University
    Harvard University
    University of North Carolina)

  • Michaela K. Welch

    (Boston University)

  • Keith A. Gagnon

    (Boston University)

  • Thijs Koorman

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Sudong Kim

    (Boston University
    Harvard University)

  • Linqing Li

    (Boston University
    Harvard University)

  • Andrea I. McClatchey

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Christopher S. Chen

    (Boston University
    Harvard University)

Abstract

The mammary gland is a highly vascularized tissue capable of expansion and regression during development and disease. To enable mechanistic insight into the coordinated morphogenic crosstalk between the epithelium and vasculature, we introduce a 3D microfluidic platform that juxtaposes a human mammary duct in proximity to a perfused endothelial vessel. Both compartments recapitulate stable architectural features of native tissue and the ability to undergo distinct forms of branching morphogenesis. Modeling HER2/ERBB2 amplification or activating PIK3CA(H1047R) mutation each produces ductal changes observed in invasive progression, yet with striking morphogenic and behavioral differences. Interestingly, PI3KαH1047R ducts also elicit increased permeability and structural disorganization of the endothelium, and we identify the distinct secretion of IL-6 as the paracrine cause of PI3KαH1047R-associated vascular dysfunction. These results demonstrate the functionality of a model system that facilitates the dissection of 3D morphogenic behaviors and bidirectional signaling between mammary epithelium and endothelium during homeostasis and pathogenesis.

Suggested Citation

  • Matthew L. Kutys & William J. Polacheck & Michaela K. Welch & Keith A. Gagnon & Thijs Koorman & Sudong Kim & Linqing Li & Andrea I. McClatchey & Christopher S. Chen, 2020. "Uncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17102-x
    DOI: 10.1038/s41467-020-17102-x
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    Cited by:

    1. Indranil Paul & Dante Bolzan & Ahmed Youssef & Keith A. Gagnon & Heather Hook & Gopal Karemore & Michael U. J. Oliphant & Weiwei Lin & Qian Liu & Sadhna Phanse & Carl White & Dzmitry Padhorny & Sergei, 2023. "Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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