The transcriptional landscape analysis of basal cell carcinomas reveals novel signalling pathways and actionable targets.
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ABSTRACT:
SUBMITTER: Litvinov IV
PROVIDER: S-EPMC8200290 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown. Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4-5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity. Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes. Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection-it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.
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Project description:Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.
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Project description:BackgroundMedulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects.MethodsWe identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB.ResultsOur analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB.ConclusionsOur findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
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