Testicular germ cell tumors arise in the absence of sex-specific differentiation
Autor: | Oscar Murillo, Denise G. Lanza, Aleksandar Milosavljevic, Susan M. Benton, Nicholas J. Webster, Emily L LaPlante, Jason D. Heaney, Rebecca L. Maywald, Emily P. Dawson |
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Rok vydání: | 2021 |
Předmět: |
Male
endocrine system Embryonal Carcinoma Stem Cells Sex Differentiation Testicular Germ Cell Tumor Nodal signaling Embryonic Germ Cells Biology medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Testicular Neoplasms medicine Animals Allele Molecular Biology Cell Proliferation 030304 developmental biology 0303 health sciences Teratoma Gene Expression Regulation Developmental RNA-Binding Proteins Cell Differentiation Neoplasms Germ Cell and Embryonal Embryonic stem cell Phenotype Spermatogonia Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis NODAL Carcinogenesis Germ cell Signal Transduction Research Article Developmental Biology |
Zdroj: | Development |
ISSN: | 1477-9129 0950-1991 |
Popis: | 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. |
Databáze: | OpenAIRE |
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