TY - JOUR
T1 - The cytoskeletal adapter protein spinophilin regulates invadopodia dynamics and tumor cell invasion in glioblastoma
AU - Cheerathodi, Mujeeburahiman
AU - Avci, Naze G.
AU - Guerrero, Paola A.
AU - Tang, Leung K.
AU - Popp, Julia
AU - Morales, John E.
AU - Chen, Zhihua
AU - Carnero, Amancio
AU - Lang, Frederick F.
AU - Ballif, Bryan A.
AU - Rivera, Gonzalo M.
AU - McCarty, Joseph H.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment. Implications: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma.
AB - Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment. Implications: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma.
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U2 - 10.1158/1541-7786.MCR-16-0251
DO - 10.1158/1541-7786.MCR-16-0251
M3 - Article
C2 - 27655131
AN - SCOPUS:85004039818
SN - 1541-7786
VL - 14
SP - 1277
EP - 1287
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -