OR27-06 Identification And Functional Analyses Of Therapeutic Targets For Testicular Germ Cell Tumors

Disclosure: K. Horie: None. S. Kitayama: None. K. Ikeda: None. T. Suzuki: None. S. Kawakami: None. S. Inoue: None. Testicular germ cell tumor (TGCT) is the most common cancer among adolescent and young adult males. While cisplatin is a key drug that efficiently reduces TGCT growth, the acquisition of drug resistance is often life-threatening. To elucidate molecular mechanisms underlying the pathophysiology of TGCT, we established patient-derived TGCT spheroid cultures from nonseminomatous tumors, in which cancer stem cell population can be preferentially enriched. The TGCT spheroid cultures can be applied to the generation of in vivo xenograft models, which successfully recapitulated the pathological features of patient tumors with microenvironment. Transcriptomic analysis revealed that hypoxia-related genes were upregulated in TGCT spheroid cultures, and HIF1α inhibitor 2-methoxyestradiol could substantially repress the in vivo tumor formation. We further generated cisplatin-resistant TGCT models from embryonic cancer patient-derived spheroids and cell line, and found that transcription-related gene high mobility group nucleosome binding domain 5 (HMGN5) and meiosis-related gene testis-expressed 11 (TEX11) were remarkably upregulated in cisplatin-resistant TGCT cells compared with their parental cells. Either HMGN5 or TEX11 knockdown could reduce the viability of cisplatin-resistant TGCT cells in the presence of cisplatin. Of note, TEX11 knockdown increased cleaved PARP1 protein expression and the percentage of double-strand break marker γH2AX-positive cells in cisplatin-resistant TGCT cells. We demonstrated that siRNA-mediated TEX11 inhibition is a promising therapeutic option for cisplatin-resistant TGCT as we showed the efficacy in in vivo xenograft models generated from cisplatin-resistant patient-derived TGCT spheroids. Furthermore, chromatin immunoprecipitation sequencing for histone H3K27 acetylation status in the TGCT spheroid cultures revealed that the enrichment of “super-enhancers”, identified by the Rank Ordering of Super-enhancers algorithm [http://younglab.wi.mit.edu/super_enhancer_code.html], was well observed at chromosome 12p, where copy number gains are often observed in the tumors, and genes in the vicinity of super-enhancers identified in patient-derived TGCT models can be potential diagnostic and therapeutic targets for the advanced disease. Overall, the present study provides useful insights into the biology and chemoresistance of TGCT. Presentation: Saturday, June 17, 2023