title: A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma.
abstract: The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing, anoikis-resistant anchorage independent (AI) phenotypes. Both phenotypes are present in established mouse and human tumors. The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI cells. A 20 fold overexpression of inhibitor of differentiation 2 (Id2) was identified in AD cells while up-regulation of genes involved in anoikis resistance like PI3K/Akt, Erk, Bcl2 and integrins was observed in AI cells. Similarly, differential expression of Id2 and other genes of interest were also observed in the AD and AI phenotypes of human neuroblastoma cell lines, SK-N-SH and IMR-32; as well as in primary human tumor specimens. Forced down-regulation of Id2 in AD cells or overexpression in AI cells induced the cells to gain characteristics of the other phenotype. Id2 binds both TGFβ and Smad2/3 and appears critical for maintaining the proliferative phenotype at least partially through negative regulation of the TGFβ/Smad pathway. Simultaneously targeting the differential molecular pathways governing reversible adaptive plasticity resulted in 50% cure of microscopic disease and delayed tumor growth in established mouse neuroblastoma tumors. We present a mechanism that accounts for reversible adaptive plasticity and a molecular basis for combined targeted therapies in neuroblastoma.
authors.affiliation: The Joseph E. Robert Center for Surgical Care, Children's National Medical Center, Washington, D.C., United States of America ; The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, D.C., United States of America.
authors.forename: Lina
authors.initials: L
authors.lastname: Chakrabarti
authors.affiliation: Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, D.C., United States of America.
authors.forename: Bi-Dar
authors.initials: BD
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, D.C., United States of America.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Lee
authors.affiliation: The Joseph E. Robert Center for Surgical Care, Children's National Medical Center, Washington, D.C., United States of America ; The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, D.C., United States of America.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Sandler
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D016212:Transforming Growth Factor beta