American Association for Cancer Research
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Supplemental Table S1 from Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

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posted on 2023-03-31, 00:27 authored by Huaibiao Li, Lucien Frappart, Jürgen Moll, Anne Winkler, Torsten Kroll, Jana Hamann, Iris Kufferath, Marco Groth, Stefan Taudien, Moritz Schütte, Marie-Laure Yaspo, Heike Heuer, Bodo M.H. Lange, Matthias Platzer, Kurt Zatloukal, Peter Herrlich, Aspasia Ploubidou

Overview of human testis biopsy samples, which were analyzed for RHAMM parameters (mRNA expression, protein localization, locus variants, allele frequencies) as well as for expression of CFIm25 and of 12 TGCT susceptibility genes.



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.