Biology subjects

Lai, A. G.

Publications and source records attributed to Lai, A. G..

12 recordsLinked to original sources

bioRxiv2021

Phylogenetic analysis of TALE superclass homeobox genes in amphipod crustaceans

TALE class genes are a group of developmentally conserved transcription factors found in animals. Here, we describe the identification and phylogenetic analysis of TALE class genes in amphipod crustaceans. We identified 241 putative TALE class genes from 56 amphipod crustacean species. Phylogenetic analysis of the genes revealed six subclasses. We provide a list of FASTA sequences of the genes identified. Results from this work may inform future evolutionary and comparative genomics studies on animal development.

evolutionary biology↗

bioRxiv2019

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogramming being a hallmark of cancer, the utility of agents targeting AMPK has received continued scrutiny and results have demonstrated conflicting effects of AMPK activation in tumorigenesis. Harnessing multi-omics datasets from human tumors, we seek to evaluate the seemingly pleiotropic, tissue-specific dependencies of AMPK signaling dysregulation. We interrogated copy number variation and differential transcript expression of 92 AMPK pathway genes across 21 diverse cancers involving over 18,000 patients. Cox proportional hazards regression and receiver operating characteristic analyses were used to evaluate the prognostic significance of AMPK dysregulation on patient outcomes. A total of 24 and seven AMPK pathway genes were identified as having loss- or gain-of-function features. These genes exhibited tissue-type dependencies, where survival outcomes in glioma patients were most influenced by AMPK inactivation. Cox regression and log-rank tests revealed that the 24-AMPK-gene set could successfully stratify patients into high- and low-risk groups in glioma, sarcoma, breast and stomach cancers. The 24-AMPK-gene set could not only discriminate tumor from non-tumor samples, as confirmed by multidimensional scaling analyses, but is also independent of tumor, node and metastasis staging. AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization. Anomalous AMPK signaling converged on similar groups of transcriptional targets where a common set of transcription factors were identified to regulate these targets. We also demonstrated crosstalk between pro-catabolic AMPK signaling and two pro-anabolic pathways, mammalian target of rapamycin and peroxisome proliferator-activated receptors, where they act synergistically to influence tumor progression significantly. Genetic and transcriptional aberrations in AMPK signaling have tissue-dependent pro- or anti-tumor impacts. Pan-cancer investigations on molecular changes of this pathway could uncover novel therapeutic targets and support risk stratification of patients in prospective trials.

cancer biology↗

bioRxiv2019

An immunoevasive strategy through clinically-relevant pan cancer genomic and transcriptomic alterations of JAK-STAT signaling components

Since its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in JAK-STAT signaling, we found that copy number alterations underpin transcriptional dysregulation that differs within and between cancer types. Integrated analyses on over 18,000 tumors representing 21 cancer types revealed a core set of 28 JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demon-strated pan-cancer molecular features associated with misex-pression of genes in other oncogenic pathways (Wnt, MAPK, TGF-{beta}, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst. Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

cancer biology↗

bioRxiv2019

Pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet, little is known about the interactions between genetic and transcriptional events of pathway genes in a pan-cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 putative driver candidates demonstrating mutually exclusive patterns of loss- and gain-of-function phenotypes. These driver genes successfully predicted patient survival rates in bladder, renal, glioma, liver and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically-relevant relationships between PPARs and hypoxia were observed where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity and hypoxia.

cancer biology↗

bioRxiv2019

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. ClockLoss and ClockGain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. ClockLoss and ClockGain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with first-line treatments.

cancer biology↗

bioRxiv2019

Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion

Background: Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies. To eradicate CSCs, parallels can be drawn from signalling modules that orchestrate pluripotency. Notch-Hedgehog hyperactivation are seen in CSCs, yet, not much is known about their conserved roles in tumour progression across cancers. Methods: Employing a comparative approach involving 21 cancers, we uncovered clinically-relevant, pan-cancer drivers of Notch and Hedgehog. GISTIC datasets were used to evaluate copy number alterations. Receiver operating characteristic and Cox regression were employed for survival analyses. Results: We identified a Notch-Hedgehog signature of 13 genes exhibiting high frequencies of somatic amplifications leading to transcript overexpression. The signature successfully predicted patients at risk of death in five cancers(n=2,278): glioma(P<0.0001), clear cell renal cell(P=0.0022), papillary renal cell(P=0.00099), liver(P=0.014) and stomach(P=0.011). The signature was independent of other clinicopathological parameters and offered additional resolution to stratify similarly-staged tumours. High-risk patients exhibited features of stemness and had more hypoxic tumours, suggesting that hypoxia may influence CSC behaviour. Notch-Hedgehog+ CSCs had an immune privileged phenotype associated with increased regulatory T cell function. Conclusion: This study will set the stage for exploring adjuvant therapy targeting the Notch-Hedgehog axis to help optimise therapeutic regimes leading to successful CSC elimination.

cancer biology↗

bioRxiv2019

Transcriptional landscape of DNA repair genes underpins a pan-cancer prognostic signature associated with cell cycle dysregulation and tumor hypoxia

Overactive DNA repair contributes to therapeutic resistance in cancer. However, pan-cancer comparative studies investigating the contribution of all DNA repair genes in cancer progression employing an integrated approach have remained limited. We performed a multicohort retrospective analysis to determine the prognostic significance of 138 DNA repair genes in 16 cancer types (n=16,225). Cox proportional hazards analyses revealed a significant variation in the number of prognostic genes between cancers; 81 genes were prognostic in clear cell renal cell carcinoma while only two genes were prognostic in glioblastoma. We reasoned that genes that were commonly prognostic in highly correlated cancers revealed by Spearmans correlation analysis could be harnessed as a molecular signature for risk assessment. A 10-gene signature, uniting prognostic genes that were common in highly correlated cancers, was significantly associated with overall survival in patients with clear cell renal cell (P<0.0001), papillary renal cell (P=0.0007), liver (P=0.002), lung (P=0.028), pancreas (P=0.00013) or endometrial (P=0.00063) cancers. Receiver operating characteristic analyses revealed that a combined model of the 10-gene signature and tumor staging outperformed either classifiers when considered alone. Multivariate Cox regression models incorporating additional clinicopathological features revealed that the signature was an independent predictor of overall survival. Tumor hypoxia is associated with adverse outcomes. Consistent across all six cancers, patients with high 10-gene and high hypoxia scores had significantly higher mortality rates compared to those with low 10-gene and low hypoxia scores. Functional enrichment analyses revealed that high mortality rates in patients with high 10-gene scores were attributable to an overproliferation phenotype. Death risk in these patients was further exacerbated by concurrent mutations of a cell cycle checkpoint protein, TP53. The 10-gene signature identified tumors with heightened DNA repair ability. This information has the potential to radically change prognosis through the use of adjuvant DNA repair inhibitors with chemotherapeutic drugs.

cancer biology↗

bioRxiv2019

Pan-cancer genomic amplifications underlie a Wnt hyperactivation phenotype associated with stem cell-like features leading to poor prognosis

Cancer stem cells pose significant obstacles to curative treatment contributing to tumor relapse and poor prognosis. They share many signaling pathways with normal stem cells that control cell proliferation, self-renewal and cell fate determination. One of these pathways known as Wnt is frequently implicated in carcinogenesis where Wnt hyperactivation is seen in cancer stem cells. Yet, the role of conserved genomic alterations in Wnt genes driving tumor progression across multiple cancer types remains to be elucidated. In an integrated pan-cancer study involving 21 cancers and 18,484 patients, we identified a core Wnt signature of 16 genes that showed high frequency of somatic amplifications linked to increased transcript expression. The signature successfully predicted overall survival rates in six cancer cohorts (n=3,050): bladder (P=0.011), colon (P=0.013), head and neck (P=0.026), pan-kidney (P<0.0001), clear cell renal cell (P<0.0001) and stomach (P=0.032). Receiver operating characteristic analyses revealed that the performance of the 16-Wnt-gene signature was superior to tumor staging benchmarks in all six cohorts and multivariate Cox regression analyses confirmed that the signature was an independent predictor of overall survival. In bladder and renal cancer, high risk patients as predicted by the Wnt signature had more hypoxic tumors and a combined model uniting tumor hypoxia and Wnt hyperactivation resulted in further increased death risks. Patients with hyperactive Wnt signaling had molecular features associated with stemness and epithelial-to-mesenchymal transition. Our study confirmed that genomic amplification underpinning pan-cancer Wnt hyperactivation and transcriptional changes associated with molecular footprints of cancer stem cells lead to increased death risks.\n\nList of Abbreviations

cancer biology↗

bioRxiv2018

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers

BackgroundDespite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.\n\nMethodsIn a retrospective bioinformatics analysis involving patients with liver cancer (n=839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n=520), renal papillary cell (n=290), lung (n=515), pancreas (n=178) and endometrial (n=370).\n\nFindingsThe 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR)=1.82, P=0.006; HR=1.84, P=0.008 and HR=2.67, P=0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR=2.36, P=0.0003; HR=2.43, P=0.0002 and HR=3.45, P=0.0007), head and neck (HR=1.64, P=0.004), renal papillary cell (HR=2.31, P=0.04), lung (HR=1.45, P=0.03), pancreas (HR=1.96, P=0.006) and endometrial (HR=2.33, P=0.003). Receiver operating characteristic analyses demonstrated both signatures superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.\n\nConclusionsThis study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n=2,712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.

cancer biology↗

bioRxiv2018

Prognostic signatures of oxygen-sensing genes predict patient survival in ten cancers including those of the liver, pancreas and stomach

ObjectivesTumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications on prognosis.\n\nMethodsWe identified of two signatures, signature 1 (good prognosis) and signature 2 (adverse prognosis), each consisting of 5 genes using three pancreatic cancer cohorts (n=681). We validated the signatures performance in predicting survival in ten cancers using Cox regression and receiver operating characteristic (ROC) analyses.\n\nResultsSignature 1 and signature 2 were associated with good and poor overall survival respectively. Prognosis of signature 1 in 8 cohorts representing 6 cancers (n=2,627): bladder (hazard ratio [HR]=0.68, P=0.039), papillary renal cell (HR=0.35, P=0.013), liver (HR=0.64, P=0.033 and HR=0.49, P=0.025), lung (HR=0.66, P=0.014) and pancreatic (HR=0.42, P<0.001 and HR=0.64, P=0.04) and endometrial (HR=0.40, P<0.001). Prognosis of signature 2 in 12 cohorts representing 9 cancers (n=4,134): bladder (HR=1.46, P=0.039), cervical (HR=1.97, P=0.035), head and neck (HR=1.39, P=0.038), renal clear cell (HR=1.47, P=0.012), papillary renal cell (HR=3.89, P=0.0015), liver (HR=5.10, P<0.0001 and HR=2.26, P<0.001), lung (HR=1.54, P=0.011), pancreatic (HR=2.09, P=0.002, HR=1.46, P=0.018, and HR=1.99, P<0.0001) and stomach (HR=1.78, P=0.004). Multivariate Cox regression confirmed independent clinical relevance of signatures in these cancers. ROC analyses confirmed superior performance of signatures to current tumor staging benchmarks. KDM8 is a potential tumor suppressor downregulated in liver and pancreatic cancers and is an independent prognostic factor. KDM8 expression negatively correlated with cell cycle regulators. Low KDM8 in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling.\n\nConclusionsPan-cancer signatures of oxygen-sensing genes used for risk assessment in 10 cancers (n=6,761) could guide individualized treatment plans.

cancer biology↗

bioRxiv2016

The innate immune systems of malacostracan crustaceans exhibit both conserved and evolutionarily distinct components

Growing demands for aquatic sources of animal proteins have attracted significant investments in aquaculture research in recent years. The crustacean aquaculture industry has undergone substantial growth to accommodate a rising global demand, however such large-scale production is susceptible to pathogen-mediated destruction. It is clear that a thorough understanding of the crustacean innate immune system is imperative for future research into combating current and future pathogens of the main food crop species. Through a comparative genomics approach utilising extant data from 55 species, we describe the innate immune system of crustaceans from the Malacostraca class. We identify 7407 malacostracan genes from 39 gene families implicated in different aspects of host defence and demonstrate dynamic evolution of innate immunity components within this group. Malacostracans have achieved flexibility in recognising infectious agents through divergent evolution and expansion of pathogen recognition receptors genes. Antiviral RNAi, Toll and JAK-STAT signal transduction pathways have remained conserved within Malacostraca, although the Imd pathway appears to lack several key components. Immune effectors such as the antimicrobial peptides (AMPs) have unique evolutionary profiles, with many malacostracan AMPs not found in other arthropod groups. Lastly, we describe four putative novel immune gene families, characterised by distinct protein domains, potentially representing important evolutionary novelties of the malacostracan immune system.

evolutionary biology↗

bioRxiv2016

Analyses of the core eukaryotic protein subunit of telomerase support extensive adaptation to different evolutionary and life histories in the Metazoa

Most animals employ telomerase, which consists of a catalytic subunit known as the telomerase reverse transcriptase (TERT) and an RNA template, to maintain telomere ends. Given the importance of TERT and the apparent importance of telomere biology in core metazoan life history traits like ageing and the control of somatic cell proliferation, we hypothesised that TERT would have patterns of sequence and regulatory evolution reflecting adaptations to diverse evolutionary and life histories across the Animal Kingdom. To test this, we performed a complete investigation of the evolutionary history of TERT across animals. We show that although TERT is almost ubiquitous across Metazoa, it has undergone substantial sequence evolution in canonical motifs. Beyond the known canonical motifs, we also identify and compare regions that are highly variable between lineages, but for which conservation exists within phyla. Recent data have highlighted the importance of alternate splice forms of TERT in non-canonical functions in some animals. Although animals may share some conserved introns, we find that the selection of exons for alternative splicing appears to be highly variable, and regulation by alternative splicing appears to be a very dynamic feature of TERT evolution. We show that even within a closely related group of triclad flatworms, where alternative splicing of TERT was previously correlated with reproductive strategy, we observe highly diverse alternative splicing patterns. Our work establishes that the evolutionary history and structural evolution of TERT involves previously unappreciated levels of change, supporting the view that this core eukaryotic protein has adapted to the requirements of diverse animal life histories.

evolutionary biology↗