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Publication of the Month | August 2021

    Home Publication of the Month Publication of the Month | August 2021

    Publication of the Month | August 2021

    By The McGowan Institute For Regenerative Medicine | Publication of the Month, Publication of the Month 2021 | 0 comment | 30 August, 2021 | 0

    Author: Sarkis Hamalian, Robert Güth, Farhana Runa, Francesca Sanchez, Eric Vickers, Megan Agajanian, Justin Molnar, Tuan Nguyen, Joshua Gamez, Jonathan D Humphries, Anupma Nayak, Martin J Humphries, Julia Tchou, Ioannis K Zervantonakis, Jonathan A Kelber

    Title: A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers

    Summary: Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in SNAI2 expression and enriched for MSC content. Specifically, we identified that the fibroblastic stroma in HER2-positive breast cancer patient tissue stains positive for both nuclear SNAI2 and cytoplasmic PEAK1. Furthermore, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells in a PEAK1-dependent manner. Analysis of PEAK1-dependent secreted factors from MSCs revealed INHBA/activin-A as a necessary factor in the conditioned media of PEAK1-expressing MSCs that promotes lapatinib resistance. Single-cell CycIF analysis of MSC-breast cancer cell co-cultures identified enrichment of p-Akthigh/p-gH2AXlow, MCL1high/p-gH2AXlow and GRP78high/VIMhigh breast cancer cell subpopulations by the presence of PEAK1-expressing MSCs and lapatinib treatment. Bioinformatic analyses on a PEAK1-centric stroma-tumor cell gene set and follow-up immunostaining of co-cultures predict targeting antiapoptotic and stress pathways as a means to improve targeted therapy responses and patient outcomes in HER2-positive breast cancer and other stroma-rich malignancies. These data provide the first evidence that PEAK1 promotes tumorigenic phenotypes through a previously unrecognized SNAI2-PEAK1-INHBA stromal cell axis.

    Source: Oncogene. 2021 Aug;40(33):5224-5235. Epub 2021 Jul 8.

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    • About Us
      • Welcome
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      • What Is Regenerative Medicine?
      • Executive Committee
      • Contact Us
      • Clinical Site
    • Our Research
      • Focus Areas
        • Tissue Engineering and Biomaterials
        • Cellular Therapies
        • Medical Devices and Artificial Organs
        • Clinical Translation
      • Matrix
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      • Clinical Trials
      • Initiatives
    • Media
      • Current News
      • News Archive
      • Video
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      • Newsletter
      • Grant of the Month
      • Publication of the Month
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