Biology subjects

Ying, H.

Publications and source records attributed to Ying, H..

24 records · Page 2Linked to original sources

bioRxiv2020

The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and, consequently, access to blood-derived nutrients and oxygen, which impacts tumor growth. Intracellular redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle, disturbs redox homeostasis and halts proliferation of PDA cells in vitro. In contrast, GOT2 inhibition has no effect on in vivo tumor growth or tumorigenesis in an autochthonous model. We propose that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts. More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Genetic or pharmacologic inhibition of pyruvate uptake or metabolism abrogated pyruvate-mediated alleviation of reductive stress from NADH buildup. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.

cancer biology↗

bioRxiv2020

Therapy-induced transdifferentiation promotes glioma growth independent of EGFR signaling

Epidermal growth factor receptor (EGFR) is frequently amplified, mutated and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical response, and the underlying mechanism remains poorly understood. Through analyses of an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals a small population of glioma cells that can evade therapy-initiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses further identify TGF{beta}/YAP/Slug signaling cascade activation as major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, the TGF{beta} secreted from the stressed glioma cells acts to promote YAP nuclear translocation and activation, which subsequently stimulates upregulation of the pro-mesenchymal transcriptional factor Slug and then glioma lineage transdifferentiation towards a stable therapy-refractory state. Blockade of this adaptive response through enforced dominant negative YAP expression significantly delayed anti-EGFR relapse and significantly prolonged animal survival. Together, our findings shed new insight into EGFR-targeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses. SignificanceThis study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and is clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas carrying aberrant EGFR signaling.

cancer biology↗

bioRxiv2020

Signatures of selection in the coral holobiont reveal complex adaptations to inshore environments driven by Holocene climate change

Climate change at the Pleistocene/Holocene boundary reshaped many coastal landscapes, and provides an opportunity to study recent adaptive processes in marine species and ecosystems including coral reefs. On the Great Barrier Reef (GBR) sea level rise flooded a vast shelf creating a distinct inshore region which now harbours extensive coral assemblages despite being subject to relatively high turbidity, freshwater input and thermal fluctuations. To investigate how the coral holobiont has adapted to these conditions we first generated a highly contiguous genome assembly for Acropora tenuis based on long-read sequencing, and then used shallow whole-genome resequencing of 148 Acropora tenuis colonies from five inshore locations to model demographic history, identify signatures of selection and profile symbiont communities. We show that corals from Magnetic Island, located in the central inshore region of the GBR, are genetically distinct from those 50-500km further north, reflecting a Pleistocene (250-600Kya) split, whereas photosymbiont genotypes differ between reefs in a pattern more likely to reflect contemporary (Holocene) conditions. We also identified loci in the coral host genome with signatures of positive selection in the northern population and used coalescent simulations to show that these are unlikely to be accounted for by demographic history. Genes at these loci have roles in a diverse range of processes that includes heterotrophic nutrition, osmotic regulation, skeletal development and the establishment and maintenance of symbiosis. Our results show that, in the case of A. tenuis holobionts from the inshore GBR, the genomes of both the coral host and the primary photosymbiont of have been significantly shaped by their environment and illustrate the complexity of adaptations that have occurred in response to past climate change.

genomics↗

bioRxiv2018

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma

Epigenetic modifiers have emerged as important regulators of tumor progression. We identified histone methyltransferase KMT2D as a potent tumor-suppressor through an in vivo epigenome-focused pooled RNAi screen in melanoma. KMT2D harbors frequent somatic point mutations in multiple tumor types. How these events contribute to tumorigenesis and whether they impart therapeutic vulnerability are poorly understood. To address these questions, we generated a genetically engineered mouse model of melanoma based on conditional and melanocyte-specific deletion of KMT2D. We demonstrate KMT2D as a bona fide tumor suppressor which cooperates with activated BRAF. KMT2D-deficient tumors showed substantial reprogramming of key metabolic pathways including glycolysis. Glycolysis enzymes, intermediate metabolites and glucose consumption rate were aberrantly upregulated in KMT2D mutant cells. The pharmacological inhibition of glycolysis reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, KMT2D loss caused drastic reduction of H3K4me1-marked active enhancer states. Loss of distal enhancer and subsequent reduction in expression of IGFBP5 activated IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating increased usage of glycolysis pathway for enhanced biomass needs via enhancer reprogramming. Our data imply that inhibition of glycolysis or IGFR pathway could be a potential therapeutic strategy in KMT2D mutant tumors.

cancer biology↗

bioRxiv2018

Simulation of Karyotype Evolution and Biodiversity in Asexual and Sexual Reproduction

Whether sexual reproduction increases biodiversity remains controversial. Traditionally, sex within a species has been thought to increase genetic diversity, inferring an acceleration of macro-evolution, promoting biodiversity. Recently, it was suggested that the main function of sex is to maintain genome integrity, rather than increase genetic diversity or purify deleterious genes within populations, as the karyotype encodes/safeguards the genomic blueprint. As such, the contribution of sex to biodiversity needs to be re-examined. Since many simulation studies focus only on gene-level selection, it is important to investigate how sexual and asexual reproduction differentially impact patterns of genome-level evolution and biodiversity. Based on the key difference between sexual and asexual reproduction, that sexual individuals are required to mate with a partner of the same genome for successful reproduction, we have performed a simulation to illustrate how such differences impact genome-mediated biodiversity. Asexual populations displayed high genome-level diversity whereas sexual populations evidenced low genome-level diversity. Further analysis demonstrated that the requirement of finding a partner possessing a compatible genome prevents new sexual species from emerging, which may explain why geographic isolation can promote speciation: by increasing mating and survival-domination opportunities. This study challenges the traditional concepts of speciation and the function of sex.

evolutionary biology↗

bioRxiv2018

YAP1 Oncogene is a Context-specific Driver for Pancreatic Ductal Adenocarcinoma

AbstractTranscriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP1 activity in human PDAC, and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.

cancer biology↗