Testicular germ cell tumors arise in the absence of sex-specific differentiation

Abstract

In response to signals from the embryonic testis, the germ cell intrinsic factor NANOS2 coordinates a transcriptional program necessary for the differentiation of pluripotent-like primordial germ cells toward a unipotent spermatogonial stem cell fate. Emerging evidence indicates that genetic risk factors contribute to testicular germ cell tumor initiation by disrupting sex-specific differentiation. Here, using the 129.MOLF-Chr19 mouse model of testicular teratomas and a NANOS2 reporter allele, we report that the developmental phenotypes required for tumorigenesis, including failure to enter mitotic arrest, retention of pluripotency and delayed sex-specific differentiation, were exclusive to a subpopulation of germ cells failing to express NANOS2. Single-cell RNA sequencing revealed that embryonic day 15.5 NANOS2-deficient germ cells and embryonal carcinoma cells developed a transcriptional profile enriched for MYC signaling, NODAL signaling and primed pluripotency. Moreover, lineage-tracing experiments demonstrated that embryonal carcinoma cells arose exclusively from germ cells failing to express NANOS2. Our results indicate that NANOS2 is the nexus through which several genetic risk factors influence tumor susceptibility. We propose that, in the absence of sex specification, signals native to the developing testis drive germ cell transformation.

Testicular cancer in mice: interplay between stem cells and endocrine insults

“…Defective spermatogenesis is observed during adult life and it needs to be understood that germ cells have a limited life span and are continuously replaced. Thus, the model proposed [ 30 ] fails to explain how neonatal insults to the germ cells could manifest disease state in adult life. They have rather shown an association suggesting that germ cells are defective in T2GCT in agreement with our hypothesis that testicular cancers initiate due to expansion of stem cells compartment and blocked differentiation (spermatogenesis).…”

“…Transition from c-Kit negative to positive spermatogonial cells is governed by an epigenetic switch which decides whether the cells undergo self-renewal or cross the point of no return (lose stemness) and initiate differentiation [ 30 ]. This is regulated by DNA methylation machinery and NP95.…”

Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis

“…In addition to driving Sertoli cell proliferation in utero , activin A production by fetal Leydig cells also promotes the timely entry of fetal germ cells into a quiescent state following sex determination ( 29 – 31 ). Quiescence occurs in an important developmental interval, coincident with important aspects of normal male germ cell differentiation that include epigenetic reprograming and loss of pluripotency, each of which can be linked with reducing the risk of tumour formation ( 32 ). We have recently discovered that activin A is an important factor regulating androgen biosynthesis in the fetal testis ( 33 ); the mechanisms and significance of these findings will be discussed below.…”

The Role of DND1 in Cancers

“…In addition, DND1 was not detected among the panel of putative prognostic and diagnostic markers of human TGCT tissues identified by proteomic techniques [51], indicating DND1 may not play a significant role in human TGCT. The functional discrepancy between mouse and human DND1 in TGCT is probably not surprising, considering that even in mouse, the increase of TGCT incidence by Dnd1 Ter is highly dependent on the strain genetic background [32] and genetic susceptibility factors other than Dnd1 Ter can also increase TGCT occurrence in mouse [45,52,53]. On the other hand, mechanistic studies indicate a link between DND1 and miRNAs that characterize human TGCTs.…”