Biology subjects

Hurley, P. J.

Publications and source records attributed to Hurley, P. J..

2 recordsLinked to original sources

bioRxiv2024

Tenascin-C potentiates Wnt signaling in thyroid cancer

Tenascin-C (TNC) is a secreted extracellular matrix protein that is highly expressed during embryonic development and re-expressed during wound healing, inflammation, and neoplasia. Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our lab has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal [~]3-5 month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We utilized bulk RNA-sequencing from three independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg-/- mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.

cancer biology↗

bioRxiv2019

Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression

Immunotherapy is a treatment for many types of cancer, primarily due to deep and durable clinical responses mediated by immune checkpoint blockade (ICB)1, 2. Prostate cancer is a notable exception in that it is generally unresponsive to ICB. The standard treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), a form of castration (CTX). ADT is initially effective, but over time patients eventually develop castration-resistant prostate cancer (CRPC). Here, we focused on defining tumor-cell intrinsic factors that contribute to prostate cancer progression and resistance to immunotherapy. We analyzed cancer cells isolated from castration-sensitive and castration-resistant prostate tumors, and discovered that castration resulted in significant secretion of Interleukin-8 (IL-8) and its likely murine homolog Cxcl15. These chemokines drove subsequent intra-tumoral infiltration with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), promoting tumor progression. PMN-MDSC infiltration was abrogated when IL-8 was deleted from prostate cancer epithelial cells using CRISPR/Cas9, or when PMN-MDSC migration was blocked with antibodies against the IL-8 receptor CXCR2. Blocking PMN-MDSC infiltration in combination with anti-CTLA-4 delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Taken together, our findings establish castration-mediated IL-8 secretion and subsequent PMN-MDSC infiltration as a key suppressive mechanism in the progression of prostate cancer. Targeting of the IL-8/CXCR2 axis around the time of ADT, in combination with ICB, represents a novel therapeutic approach to delay prostate cancer progression to advanced disease.

cancer biology↗