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"Shen, Michael"
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What to eat when : a strategic plan to improve your health & life through food
\"This guide reveals how to use food to enhance our personal and professional lives--and increase longevity to boot\"-- Provided by publisher.
Book
NSD2 is a conserved driver of metastatic prostate cancer progression
Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell-intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression. Cross-species master regulator analyses comparing this mouse signature with a comparable human signature identifies conserved drivers of metastatic progression with demonstrable clinical and functional relevance. In particular,
nuclear receptor binding SET Domain Protein 2
(
NSD2
) is robustly expressed in lethal prostate cancer in humans, while its silencing inhibits metastasis of mouse allografts in vivo. We propose that cross-species analysis can elucidate mechanisms of metastasis progression, thus providing potential additional therapeutic opportunities for treatment of lethal prostate cancer.
Identifying cell intrinsic mechanisms promoting metastasis are necessary to develop new cancer therapeutics. Here they do cross-species computational analysis and identify nuclear receptor binding
SET domain Protein 2 (NSD2)
as a driver of prostate cancer metastasis.
Journal Article
Challenges of early detection of pancreatic cancer
Pancreatic cancer (PC) is a devastating disease, due in part to its diagnosis frequently being made at an advanced stage. Ongoing efforts are aimed at identifying early-stage PC in high-risk individuals, as early detection leads to downstaging of PC and improvements in survival. However, there are a myriad of challenges that arise when trying to optimize PC early detection strategies, including selection of the appropriate high-risk individuals and selection of the test or combination of tests that should be performed. Here, we discuss the populations that are the strongest candidates for PC screening and review professional PC screening guidelines. We also summarize the current state of imaging techniques for early detection of PC and further review many studied biomarkers - ranging from nucleic acid targets, proteins, and the microbiome - to highlight the current state of the field and the challenges that remain in the years to come.
Journal Article
Differentiation of human and murine induced pluripotent stem cells to microglia-like cells
Pandya
et al
. describe a protocol to differentiate human and mouse iPSCs into cells with the phenotype, transcriptional profile and functional properties of microglia. The treatment of murine intracranial malignant gliomas with these cells demonstrates their potential clinical use. These microglia-like cells will enable further studies into the role of microglia in health and disease.
Microglia are resident inflammatory cells of the CNS and have important roles in development, homeostasis and a variety of neurologic and psychiatric diseases. Difficulties in procuring human microglia have limited their study and hampered the clinical translation of microglia-based treatments shown to be effective in animal disease models. Here we report the differentiation of human induced pluripotent stem cells (iPSC) into microglia-like cells by exposure to defined factors and co-culture with astrocytes. These iPSC-derived microglia have the phenotype, gene expression profile and functional properties of brain-isolated microglia. Murine iPSC-derived microglia generated using a similar protocol have equivalent efficacy to primary brain-isolated microglia in treatment of murine syngeneic intracranial malignant gliomas. The ability to generate human microglia facilitates the further study of this important CNS cell type and raises the possibility of their use in personalized medicine applications.
Journal Article
A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors
Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here, we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.
Journal Article
Single luminal epithelial progenitors can generate prostate organoids in culture
The intrinsic ability to exhibit self-organizing morphogenetic properties in
ex vivo
culture may represent a general property of tissue stem cells. Here we show that single luminal stem/progenitor cells can generate prostate organoids in a three-dimensional culture system in the absence of stroma. Organoids generated from CARNs (castration-resistant Nkx3.1-expressing cells) or normal prostate epithelia exhibit tissue architecture containing luminal and basal cells, undergo long-term expansion in culture and exhibit functional androgen receptor signalling. Lineage-tracing demonstrates that luminal cells are favoured for organoid formation and generate basal cells in culture. Furthermore, tumour organoids can initiate from CARNs after oncogenic transformation and from mouse models of prostate cancer, and can facilitate analyses of drug response. Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify
in vitro
approaches for studying prostate biology.
Shen and colleagues report the
in vitro
generation of organoids from mouse luminal epithelial progenitor cells and normal or transformed prostate tissue, and extend this approach to the formation of normal and tumour organoids of human origin
Journal Article
Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A
Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.
Journal Article
Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity
A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected assay dependence of their stem cell properties in sphere formation and transplantation assays versus genetic lineage tracing during prostate regeneration and adult tissue homeostasis. Although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, cross-species bioinformatic analyses indicate that tumours of luminal origin are more aggressive than tumours of basal origin, and identify a molecular signature associated with patient outcome. Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer.
Shen and colleagues find that initiation of prostate tumours by basal or luminal epithelial cells in mice leads to distinct tumour signatures. Interestingly, they find that although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, tumours of luminal origins are more aggressive in functional tests and the distinct signature correlated with that of patients with aggressive tumours.
Journal Article
The regulatory architecture of the primed pluripotent cell state
Despite extensive research, the gene regulatory architecture governing mammalian cell states remains poorly understood. Here we present an integrative systems biology approach to elucidate the network architecture of primed state pluripotency. Using an unbiased methodology, we identified and experimentally confirmed 132 transcription factors as master regulators (MRs) of mouse epiblast stem cell (EpiSC) pluripotency, many of which were further validated by CRISPR-mediated functional assays. To assemble a comprehensive regulatory network, we silenced each of the 132 MRs to assess their effects on the other MRs and their transcriptional targets, yielding a network of 1273 MR → MR interactions. Network architecture analyses revealed four functionally distinct MR modules (communities), and identified key Speaker and Mediator MRs based on their hierarchical rank and centrality. Our findings elucidate the de-centralized logic of a “communal interaction” model in which the balanced activities of four MR communities maintain primed state pluripotency.
The architecture of gene regulatory networks that govern mammalian cells has been poorly understood. Here, Li et al. present a computational systems approach to elucidate the regulatory logic of the gene network for primed state pluripotency.
Journal Article
Heterozygous diploid and interspecies SCRaMbLEing
SCRaMbLE (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution) is a genome restructuring technique that can be used in synthetic genomes such as that of Sc2.0, the synthetic yeast genome, which contains hundreds to thousands of strategically positioned loxPsym sites. SCRaMbLE has been used to induce rearrangements in yeast strains harboring one or more synthetic chromosomes, as well as plasmid DNA in vitro and in vivo. Here we describe a collection of heterozygous diploid strains produced by mating haploid semisynthetic Sc2.0 strains to haploid native parental strains. We subsequently demonstrate that such heterozygous diploid strains are more robust to the effects of SCRaMbLE than haploid semisynthetic strains, rapidly improve rationally selected phenotypes in SCRaMbLEd heterozygous diploids, and establish that multiple sets of independent genomic rearrangements are able to lead to similar phenotype enhancements. Finally, we show that heterozygous diploid SCRaMbLE can also be carried out in interspecies hybrid strains.
SCRaMbLE has been used to rearrange synthetic chromosomes that have been introduced into host yeast. Here the authors produce semi-synthetic heterozygous diploid strains for rapid selection of phenotypes and map the rearrangements underlying selected phenotypes such as thermoresistance and caffeine resistance.
Journal Article