Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.non-seminoma | SMAD | teleost | haplotype

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Cancer cells have high metabolic demands. Myc oncoproteins function as transcription factors and are overexpressed in a number of human malignancies. Myc induces the transcription of a number of genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are dependent on and utilize L-glutamine to feed carbon intermediates into the Krebs Cycle. We reasoned that Myc would also control the catabolism of BCAA, which also provides key metabolic intermediates, specifically acetoacetate, acetyl-CoA, proprionyl-CoA, NADH and FADH2. Consistent with this notion, expression analysis of premalignant and neoplastic B cells of Eμ-Myc transgenic mice, a validated model of human B cell lymphomas with Myc involvement, showed elevated mRNA and protein levels of BCAT1, which is a bona fide Myc transcription target and the first enzyme in BCAA catabolism. Further, elevated levels of several other enzymes involved in BCAA catabolism manifest in Eμ-Myc B cells. To assess the role of BCAT1 in tumor cell growth and survival, human B cell lymphoma and ovarian tumor cell lines that express high levels of BCAT1 were engineered to inducibly express shRNA that selectively silences BCAT1 expression. Notably, BCAT1 knockdown impaired tumor cell growth and survival, and long-term clonogenic growth. Moreover, treatment of Eμ-Myc B cells and BCAT1 overexpressing human tumor lines with a known BCAT1 inhibitor, Gabapentin, compromises growth and survival. Finally, the roles of BCAT1 in tumor maintenance in vivo will be presented. These findings lay the foundation for targeting BCAA catabolism in human tumors and tumor subtypes having MYC/MYCN involvement. Citation Format: Mario R. Fernandez, Vanessa A. Damoulis, Wei Wang, Bernhard Radlwimmer, John L. Cleveland. The role of branched-chain amino acid metabolism in Myc-driven malignancies. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A08.