Browsing by Author "Brasil da Costa, Fabio Henrique"

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    Role of SULF1 in the regulation of metastatic prostate cancer progression
    (2020-04-24) Brasil da Costa, Fabio Henrique; Carson, Daniel D; Warmflash, Aryeh
    The establishment of new prostate cancer (PCa) metastases in the bone marrow accompanies a classical stromal reaction orchestrated primarily by the bidirectional engagement of cancer cells and fibroblasts. As result, tumor-associated macrophages (TAMs) are recruited to the tumor and display a fluid spectrum of behaviors that may promote or suppress tumor progression. These stromal and immune reactions, although initially in place to constrain tumor growth, have been shown to ultimately benefit cancer cells, for example, due to increased bioavailability of growth factors and matrix remodeling. Also, deposition of the heparan sulfate (HS) proteoglycan perlecan (HSPG2) and secretion of HS-modifying enzymes are increased in the matrix as result of the Cancer-CAF-TAM trialogue. In this work, to investigate PCa bone metastases, we developed a novel, bone marrow mimetic hydrogel containing collagen type I, hyaluronic acid, and HS-decorated domain 1 of perlecan (COL1-HA-PlnDm1). Our goal was to use this model to study the prevalence and role of growth factor-releasing enzymes, like sulfatases 1 and 2 (SULF1/SULF2) and heparanase. We first demonstrated that PCa cells, bone marrow fibroblasts, and Mφs have excellent viability, show in vivo-like morphology, and exhibit classical phenotypic markers in COL1-HA-PlnDm1 hydrogels. Furthermore, we found that SULF1 is the major HS modifier and is predominantly expressed by activated fibroblasts both in vivo and in vitro. Then, we discovered that TAMs are highly prevalent in PCa bone marrow metastases, as indicated by CD163 and CD206 expression, and Mφs in 3D displayed similar phenotype. Additionally, alternatively activated macrophages induced upregulation of SULF1 and HSPG2 in fibroblasts in vitro. Finally, our 3D triculture data shows that when SULF1 is knocked out from fibroblasts, PCa cell proliferation and cluster volume are significantly increased in response to treatment with Wnt3a, even in the presence of Mφs. We conclude that 1) our 3D hydrogel model is a physiologically relevant in vitro system to discover fundamental aspects of HS signaling in the tumor microenvironment; and 2) the dynamics of SULF1 expression and activity suggest a tumor suppressing role in the context of Wnt3a signaling in PCa. Further studies are necessary to determine SULF1’s value as a prognostic marker or a candidate target for new therapies.