title: Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma.
abstract: Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM-a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self-renewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382-95. ©2016 AACR.
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Huaibiao
authors.initials: H
authors.lastname: Li
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.|INSERM, Oncogenèse et Progression Tumorale, Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Lucien
authors.initials: L
authors.lastname: Frappart
authors.affiliation: Forschungszentrum Karlsruhe, Institut für Toxicologie und Genetik, Karlsruhe, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Moll
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Winkler
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kroll
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Hamann
authors.affiliation: Christian Doppler Laboratory for Biospecimen Research and Biobanking Technologies, Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Kufferath
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Taudien
authors.affiliation: Alacris Theranostics GmbH, Berlin, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Schütte
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Heuer
authors.affiliation: Alacris Theranostics GmbH, Berlin, Germany.|Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bodo M H
authors.initials: BM
authors.lastname: Lange
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.affiliation: Christian Doppler Laboratory for Biospecimen Research and Biobanking Technologies, Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.|Forschungszentrum Karlsruhe, Institut für Toxicologie und Genetik, Karlsruhe, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany. aspasia.ploubidou@leibniz-fli.de.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Ploubidou
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000502:physiology*; D005298:Fertility; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000502:physiology*; D008297:Male; D051379:Mice; D009373:Neoplasms, Germ Cell and Embryonal / Q000209:etiology* / Q000473:pathology; D018239:Seminoma / Q000209:etiology* / Q000473:pathology; D008941:Spindle Apparatus / Q000737:chemistry*; D013736:Testicular Neoplasms / Q000209:etiology* / Q000473:pathology; D013737:Testis / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D016159:Tumor Suppressor Protein p53; C098946:hyaluronan-mediated motility receptor