Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype.
Scientific reports. 2022 Nov 07*** epublish ***
Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D Shields, Stephen Lin, Peter McCue, Andrew V Kossenkov, Yanqing Wang, David W Goodrich, Sheng-Yu Ku, Himisha Beltran, William K Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C Altieri, Edward F Plow, Lucia R Languino
Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA., Department of Medicine, School of Medicine, MetroHealth Medical Center, Rammelkamp Center for Research, Case Western Reserve University, Cleveland, OH, USA., Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA., Center for Systems and Computational Biology, Wistar Institute, Philadelphia, PA, USA., Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA., Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Institute of Neurochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA., Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA., Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA. .