Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.
Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with self-renewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21(WAF1/CIP1), a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; Case Western Reserve University School of Medicine, Cleveland, Ohio 44195, USA; Department of Cell Biology, Case Western Reserve University, Cleveland, Ohio 44195, USA;
Kenneth
K
Yan
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Qiulian
Q
Wu
Case Western Reserve University School of Medicine, Cleveland, Ohio 44195, USA;
Diana H
DH
Yan
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44195, USA;
Christine H
CH
Lee
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Nasiha
N
Rahim
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; Department of Neurology, University Hospital Zurich, Zurich 8091, Switzerland.
Isabel
I
Tritschler
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Jennifer
J
DeVecchio
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Matthew F
MF
Kalady
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Anita B
AB
Hjelmeland
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
Jeremy N
JN
Rich
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
BMP antagonists; Gremlin1; bone morphogenetic proteins (BMPs); cancer stem cells; glioblastoma; stem cell hierarchies