@article{1273e1cbf218428eacf449a11cd42e21,
title = "NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth",
abstract = "BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the receptor to transmit critical growth signaling. NELL2 signaling inhibits cdc42 and upregulates BAF complexes and EWS-FLI1 transcriptional output. We demonstrate that cdc42 is a negative regulator of BAF complexes, inducing actin polymerization and complex disassembly. Furthermore, we identify NELL2highCD133highEWS-FLI1high and NELL2lowCD133lowEWS-FLI1low populations in Ewing sarcoma, which display phenotypes consistent with high and low NELL2 signaling, respectively. We show that NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate BAF complexes and cell proliferation in Ewing sarcoma. These results reveal a signaling pathway regulating critical chromatin remodeling complexes and cancer cell proliferation.",
keywords = "BAF complex, CD133, Ewing sarcoma, NELL2, Robo3, cdc42, secretome proteomics",
author = "Panneerselvam Jayabal and Fuchun Zhou and Xiufen Lei and Xiuye Ma and Barron Blackman and Weintraub, {Susan T.} and Houghton, {Peter J.} and Yuzuru Shiio",
note = "Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We thank Patrick Grohar and Javed Khan for cell lines. We thank the Cooperative Human Tissue Network for Ewing sarcoma tumor RNA samples, the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo ad Dana Molleur) for mass spectrometry analysis, the UTHSCSA flow cytometry facility for flow cytometry analysis, and the UTHSCSA Histology/Immunohistochemistry Laboratory for immunohistochemistry analysis. This work was supported by the National Cancer Institute ; the National Institutes of Health ( CA202485 to Y.S. and CA165995 to P.J.H.); the Cancer Prevention and Research Institute of Texas ( RP160487 , RP160841 , and RP190385 to Y.S. and RP160716 to P.J.H.); the Owens Medical Research Foundation (to Y.S.); the National Center for Advancing Translational Sciences ; National Institutes of Health, through the Clinical and Translational Science Award (CTSA) UL1 TR001120 ; the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute ( CA054174 ) for the mass spectrometry and the flow cytometry shared resources; and the National Institutes of Health for purchase of the Orbitrap mass spectrometer ( 1S10RR025111-01 to S.T.W.). Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We thank Patrick Grohar and Javed Khan for cell lines. We thank the Cooperative Human Tissue Network for Ewing sarcoma tumor RNA samples, the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo ad Dana Molleur) for mass spectrometry analysis, the UTHSCSA flow cytometry facility for flow cytometry analysis, and the UTHSCSA Histology/Immunohistochemistry Laboratory for immunohistochemistry analysis. This work was supported by the National Cancer Institute; the National Institutes of Health (CA202485 to Y.S. and CA165995 to P.J.H.); the Cancer Prevention and Research Institute of Texas (RP160487, RP160841, and RP190385 to Y.S. and RP160716 to P.J.H.); the Owens Medical Research Foundation (to Y.S.); the National Center for Advancing Translational Sciences; National Institutes of Health, through the Clinical and Translational Science Award (CTSA) UL1 TR001120; the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174) for the mass spectrometry and the flow cytometry shared resources; and the National Institutes of Health for purchase of the Orbitrap mass spectrometer (1S10RR025111-01 to S.T.W.). P.J. and Y.S. designed the research; P.J. F.Z. X.L. X.M. B.B. S.T.W. P.J.H. and Y.S. performed the research; P.J. F.Z. B.B. S.T.W. P.J.H. and Y.S. analyzed the data; and P.J. and Y.S. wrote the paper, with input from the other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jul,
day = "6",
doi = "10.1016/j.celrep.2021.109254",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}