The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer

Abstract

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.

Targeting the αVβ3/NgR2 pathway in neuroendocrine prostate cancer

“…We have previously shown that high levels of αVβ3 increase the expression of NgR2, a novel αVβ3 binding partner and NE marker regulator in PrCa cells [ 34 ]. To further investigate whether NgR2 affects cell attachment to αVβ3 ligands, we used adhesion assays [ 34 ]. First, we tested the expression of the following epitopes of αVβ3: LIBS1, 2 and 6.…”

“…Although multiple datasets show increased levels of RTN4RL2 (the gene encoding NgR2) RNA in advanced PrCa patients [ 34 ], the role of NgR2 in NE cancer progression was not explored before our paper was published [ 34 ] and had never been analyzed in sEVs. Because NEPrCa is characterized by late diagnosis, based on metastatic biopsy in patients with spread aggressive disease with low or absent PSA levels [ 69 ], NgR2 may represent a promising, specific marker for a non-invasive diagnosis.…”

“…We have recently shown that the expression of the αVβ3 integrin, which is highly expressed in human sEVs, increases the levels of NgR2 (Nogo-66 receptor homolog 1) [ 32 , 33 ] in PrCa cells [ 34 ]. We also demonstrated that NgR2 induces neuroendocrine differentiation (NED) in recipient cells [ 34 ].…”

“…We have recently shown that the expression of the αVβ3 integrin, which is highly expressed in human sEVs, increases the levels of NgR2 (Nogo-66 receptor homolog 1) [ 32 , 33 ] in PrCa cells [ 34 ]. We also demonstrated that NgR2 induces neuroendocrine differentiation (NED) in recipient cells [ 34 ]. NgR2 belongs to the Nogo receptor family, which includes NgR1 and NgR3; these structurally related molecules are glycosylphosphatidylinositol (GPI)-anchored receptors, lacking both the transmembrane and the intracellular domains [ 32 , 33 ].…”

“…The bond between members of the NgR family and MAG triggers a signal transduction complex activating several downstream pathways [ 32 , 37 – 39 ], mainly associated with neuronal growth [ 40 ]. Multiple datasets, analyzed in Quaglia et al [ 34 ] show increased levels of RTN4RL2 (the gene encoding NgR2) RNA in advanced PrCa tumors; however, the role of NgR2 has been examined predominantly in neuroscience studies, minimally in cancer, and never in EVs.…”