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  Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Li, H., Frappart, L., Moll, J., Winkler, A., Kroll, T., Hamann, J., et al. (2016). Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma. Cancer research: an official organ of the American Association for Cancer Research, 76(21), 6382-6395. doi:10.1158/0008-5472.CAN-16-0179.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-BC8A-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-BC8B-0
Genre: Journal Article

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© 2016 American Association for Cancer Research
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 Creators:
Li, H., Author
Frappart, L., Author
Moll, J., Author
Winkler, A., Author
Kroll, T., Author
Hamann, J., Author
Kufferath, I., Author
Groth, M., Author
Taudien, S., Author
Schütte, M., Author
Yaspo, M. L.1, Author              
Heuer, H., Author
Lange, B. M., Author
Platzer, M., Author
Zatloukal, K., Author
Herrlich, P., Author
Ploubidou, A., Author
Affiliations:
1Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              

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Free keywords: Animals Apoptosis Cell Division Extracellular Matrix Proteins/analysis/*physiology *Fertility HeLa Cells Humans Hyaluronan Receptors/analysis/*physiology Male Mice Neoplasms, Germ Cell and Embryonal/*etiology/pathology Seminoma/*etiology/pathology Spindle Apparatus/*chemistry Testicular Neoplasms/*etiology/pathology Testis/*cytology Tumor Suppressor Protein p53/physiology
 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. (c)2016 AACR.

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Language(s): eng - English
 Dates: 2016-08-192016-11-01
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1158/0008-5472.CAN-16-0179
ISSN: 1538-7445 (Electronic)0008-5472 (Print)
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Title: Cancer research : an official organ of the American Association for Cancer Research
  Other : Cancer Res.
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Waverly Press
Pages: - Volume / Issue: 76 (21) Sequence Number: - Start / End Page: 6382 - 6395 Identifier: ISSN: 0008-5472
CoNE: /journals/resource/991042743115962