MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with various biological functions, including neuronal migration, cell polarity, microtubule dynamics, apoptosis, and cell cycle regulation, specifically in the G1/S checkpoint, cell signaling, and differentiation. It plays a critical role in different types of cancers. Hepatocellular carcinoma (HCC) is the one of the most common forms of liver cancer caused due to mutations, epigenetic aberrations, and altered gene expression patterns. Here, we have applied an integrated network biology approach to see the potential links of MARK4 in HCC, and subsequently identified potential herbal drugs. This work focuses on the naturally-derived compounds from medicinal plants and their properties, making them targets for potential anti-hepatocellular treatments. We further analyzed the HCC mutated genes from the TCGA database by using cBioPortal and mapped out the MARK4 targets among the mutated list. MARK4 and Mimosin, Quercetin, and Resveratrol could potentially interact with critical cancer-associated proteins. A set of the hepatocellular carcinoma altered genes is directly the part of infection, inflammation, immune systems, and cancer pathways. Finally, we conclude that among all these drugs, Gingerol and Fisetin appear to be the highly promising drugs against MARK4-based targets, followed by Quercetin, Resveratrol, and Apigenin.

/pdf/a-network-guided-approach-to-discover-phytochemical-based-2gb89h1a.pdf

A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma

Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative, quiescent or "dormant" state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to uniquely identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show dormancy preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We uncover novel genomic dependencies of this process, including the amplification of the centrosomal gene CEP89 as a driver of dormancy impairment. Lastly, we demonstrate that dormancy underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a signature of dormancy-linked therapeutic resistance to further study and clinically track this state.

/pdf/genomic-hallmarks-of-cellular-dormancy-in-cancer-and-43ebtfzpu4.pdf

Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

Single nucleotide variants are the commonest genetic alterations in the human genome. At least 60,000 have been reported to be associated with disease. The CRISPR/Cas9 system has transformed genetic research, making it possible to edit single nucleotides and study the function of genetic variants in vitro. While significant advances have improved the efficiency of CRISPR/Cas9, the editing of single nucleotides remains challenging. There are two major obstacles: low efficiency of accurate editing and the isolation of these cells from a pool of cells with other editing outcomes. We present data from 85 transfections of induced pluripotent stem cells and an immortalised cell line, comparing the effects of altering CRISPR/Cas9 design and experimental conditions on rates of single nucleotide substitution. We targeted variants in TP53, which predispose to several cancers, and in TBXT which is implicated in the pathogenesis of the bone cancer, chordoma. We describe a scalable and adaptable workflow for single nucleotide editing that incorporates contemporary techniques including Illumina MiSeq sequencing, TaqMan qPCR and digital droplet PCR for screening transfected cells as well as quality control steps to mitigate against common pitfalls. This workflow can be applied to CRISPR/Cas9 and other genome editing systems to maximise experimental efficiency. Simple SummaryCRISPR/Cas9 has revolutionised genetic research. Cas9 generates a double strand break with high efficiency which is repaired by a cells pathways. If a genetic template is provided, the damage can be accurately repaired to introduce a desired genetic alteration. However, accurate repair occurs at a low efficiency and in a small proportion of edited cells, representing the main obstacles in harnessing CRISPRs full potential. Using data from 85 CRISPR experiments for single nucleotide editing, targeting three locations in the human genome that are implicated in predisposition to cancer, we report the effect of different experimental conditions on editing efficiency. We describe current technologies that can be used to streamline the identification of accurately edited cells and synthesise these into an adaptable workflow that can be applied to CRISPR/Cas9 experiments to achieve single nucleotide editing in disease-relevant cell models.

https://biorxiv.org/content/10.1101/2021.11.12.467071v1.full.pdf

An efficient and adaptable workflow for editing disease-relevant single nucleotide variants using CRISPR/Cas9

The treatment options for central chondrosarcoma are limited, and prognoses are generally unreliable. The presence and absence of mutations in IDH1, and IDH2 are defining events, and TERT mutations have been recently been associated with poor outcome. Despite this, molecular biomarkers are lacking. Here, analysing data from 356 patients, comprising results from whole genome sequencing (n=68), digital droplet PCR (n=346), and methylation arrays (n=57), we present a comprehensive genetic analysis of chondrosarcoma and suggest its clinical utility. Methylation profiles, TERT promoter mutations, genome doubling with prior haploidisation, and age at diagnosis of high grade, distinguish IDH1-mutant, IDH2-mutant and IDH wildtype tumours. The majority of IDH2-mutant tumours harbour TERT mutations, though a significant reduction in survival is only found in the less common mutational combination of IDH1 and TERT. We suggest that diagnostic testing for IDH1, IDH2 and TERT mutations could guide clinical monitoring and prognostication.

https://medrxiv.org/content/10.1101/2021.11.02.21265785v1.full.pdf

A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome

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Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

An efficient and adaptable workflow for editing disease-relevant single nucleotide variants using CRISPR/Cas9

A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome