Date: Saturday, June 1, 2019
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: Liver transplantation (LT) can cure locally invasive, unresectable and chemo-resistant hepatoblastoma (HBL), an embryonal liver tumor of infancy. Post-LT immunosuppression enhances recurrence-risk despite chemotherapy.
*Methods: Toward the long term goal of enhancing efficacy of chemotherapy by identifying novel targets and pathways, we conducted a systems biology analysis of the exome and transcriptome of 11 HBL tumors removed at LT using protein interaction maps and transcriptional regulatory pathways.
*Results: Integrative analysis was performed using the beta-catenin gene and 78 other genes all of which harbored single nucleotide variants (SNVs), 26 genes with copy number variants (CNVs) and 6564 differentially expressed (DE) genes (≥2-fold change, q-value <0.05). Analysis of genes with CNVs revealed dysregulated (p<10E-04, Fisher's test) 1. Autophagy - hub of gene RB1CC1 with nine DE gene connections; 2. Cell growth, development, differentiation or histone modifications -hub of gene JAK2 with 48 DE gene connections, 14 SNVs and 3 CNVs; 3. Cell Proliferation - hub of gene TTK with 15 DE gene connections, with 1 SNV; 4. GPCR signaling - hub of gene ADCY9 with 8 DE gene connections. K-means clustering of DE genes with SNVs and 23 of their 54 first neighbor connections, which were also DE genes revealed enrichment of 4 distinct clusters (p-value<10E-4): ciliary function, ion channel and gating activity, calcium processing and complex signaling assembly. Of 304 known ciliary genes [SYSCILIA gold database], 81 were DE in HBL tumors (over 70% upregulated, remaining downregulated) and were enriched for ciliary assembly, organization and morphogenesis (p<10E-40). Two HBL tumors that led to fatal recurrence harbored CNV losses in the transmembrane protein 192, TMEM192 (4q32.3, chr4:165997231-166000948, 3719bp) and TRIM60 (4q32.3, chr4:165961221-165962896, 1677bp) genes, which bind key pioneer and lineage specification transcription factors (TFs) TEAD2, HIF1A, NFKB1, MYC, STAT3, RXRA (TMEM192) and E2F1, FOXF2, FOXA1, PITX2, MTF1 (TRIM60). These TFs were also DE in the tumor transcriptome as were 350 gene targets of these TFs. Non-motile primary cilia which are present on nearly all cells are known to maintain normal cell-microenvironment communication. These cilia disassemble in mitotic cancer cells and share cilia-associated autophagy, Wnt-beta-catenin and calcium signaling pathways with motile cilia. Motile cilia promote orderly morphogenesis during embryonal development, and are present on epithelial and embryonal cells, both of which are present in HBL tumors.
*Conclusions: Dysregulated ciliary, autophagy and cell-cycling pathways likely contribute to local invasiveness and chemo-resistance of unresectable HBL and may serve as novel drug targets.
To cite this abstract in AMA style:Narayanan T, Ningappa M, Higgs BW, Subramaniam S, Sindhi R. Hepatoblastoma Tumors Requiring Liver Transplantation Manifest Dysregulated Ciliary, Autophagy and Cell Cycling Pathways in Systems Biology Analysis [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/hepatoblastoma-tumors-requiring-liver-transplantation-manifest-dysregulated-ciliary-autophagy-and-cell-cycling-pathways-in-systems-biology-analysis/. Accessed January 16, 2021.
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