GAGE-seq concurrently profiles multiscale 3D genome organization and gene expression in single cells.

The organization of mammalian genomes features a complex, multiscale three-dimensional (3D) architecture, whose functional significance remains elusive because of limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we introduce genome architecture and gene expression by sequencing (GAGE-seq), a scalable, robust single-cell co-assay measuring 3D genome structure and transcriptome simultaneously within the same cell. Applied to mouse brain cortex and human bone marrow CD34 cells, GAGE-seq characterized the intricate relationships between 3D genome and gene expression, showing that multiscale 3D genome features inform cell-type-specific gene expression and link regulatory elements to target genes.

Concurrent profiling of multiscale 3D genome organization and gene expression in single mammalian cells.

The organization of mammalian genomes within the nucleus features a complex, multiscale three-dimensional (3D) architecture. The functional significance of these 3D genome features, however, remains largely elusive due to limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we report GAGE-seq, a highly scalable, robust single-cell co-assay that simultaneously measures 3D genome structure and transcriptome within the same cell.

Androgen-regulated stromal complement component 7 (C7) suppresses prostate cancer growth.

The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates.

Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity.

Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity.

Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130.

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN).

Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1 prostate luminal cells.

Prostate adenocarcinoma undergoes neuroendocrine differentiation to acquire resistance toward antihormonal therapies. The underlying mechanisms have been investigated extensively, among which Sox2 has been shown to play a critical role. However, genetic evidence in mouse models for prostate cancer to support the crucial role of Sox2 is missing.

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc.

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2 human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate.

The Sca-1 and Sca-1 mouse prostatic luminal cell lineages are independently sustained.

The phenotypic and functional heterogeneity of the mouse prostate epithelial cell lineages remains incompletely characterized. We show that the Sca-1 luminal cells at the mouse proximal prostate express Sox2. These cells are replicative quiescent, castration resistant, and do not possess secretory function.

Long non-coding RNA mortal obligate RNA transcript suppresses tumor cell proliferation in prostate carcinoma by inhibiting glucose uptake.

A previous study reported the decreased expression of long non-coding RNA mortal obligate RNA transcript (lncRNA MORT) in 16 types of cancer, while the functionality of lncRNA MORT in cancer biology remains unknown. Therefore, the present study was conducted to characterize the functionality of lncRNA MORT in prostate carcinoma, a common cancer type worldwide. lncRNA MORT expression level was downregulated in tumor tissues compared with that in the adjacent healthy tissues of patients with prostate carcinoma.

The deregulation of miR-133b is associated with poor prognosis in bladder cancer.

Background: MicroRNAs (miRNAs) are single-stranded, endogenous, non-coding RNAs that are increased or decreased in almost all cancer types, and they paly crucial roles in the tumorigenesis as well as development.

Materials And Methods: 90 patients diagnosed with bladder cancer were enrolled in the present study. The bladder cancer tissues or adjacent normal tissues were obtained from the tumor area or adjacent normal zone.

Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states.

Triple-negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer-related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal-like and epithelial-like states have been revealed in breast CSCs.

An autocrine inflammatory forward-feedback loop after chemotherapy withdrawal facilitates the repopulation of drug-resistant breast cancer cells.

Stromal cells, infiltrating immune cells, paracrine factors and extracellular matrix have been extensively studied in cancers. However, autocrine factors produced by tumor cells and communications between autocrine factors and intracellular signaling pathways in the development of drug resistance, cancer stem-like cells (CSCs) and tumorigenesis have not been well investigated, and the precise mechanism and tangible approaches remain elusive. Here we reveal a new mechanism by which cytokines produced by breast cancer cells after chemotherapy withdrawal activate both Wnt/β-catenin and NF-κB pathways, which in turn further promote breast cancer cells to produce and secrete cytokines, forming an autocrine inflammatory forward-feedback loop to facilitate the enrichment of drug-resistant breast cancer cells and/or CSCs.

Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia.

Chronic myeloid leukemia (CML) treatment with BCR-ABL inhibitors is often hampered by development of drug resistance. In a screen for novel chemotherapeutic drug candidates with genotoxic activity, we identified a bisindolylmaleimide derivative, IX, as a small molecule compound with therapeutic potential against CML including drug-resistant CML. We show that Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, activates the Atm-p53 and Atm-Chk2 pathways, and induces cell cycle arrest and cell death.

The other face of TLR3: A driving force of breast cancer stem cells.

Activation of TLR3 has long been studied in the field of anticancer immunotherapy. Our recent work revealed that TLR3 also promotes the induction of breast cancer stem cells (CSCs) through co-activation of β-catenin and NF-κB signaling. Targeting these 2 pathways simultaneously instead of individually allows for effective inhibition of CSCs that are enhanced by TLR3 activation.

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy.

Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development.

Cardamonin reduces chemotherapy-enriched breast cancer stem-like cells in vitro and in vivo.

The failure of cytotoxic chemotherapy in breast cancers has been closely associated with the presence of drug resistant cancer stem cells (CSCs). Thus, screening for small molecules that selectively inhibit growth of CSCs may offer great promise for cancer control, particularly in combination with chemotherapy. In this report, we provide the first demonstration that cardamonin, a small molecule, selectively inhibits breast CSCs that have been enriched by chemotherapeutic drugs.

MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation.

The molecules and mechanisms pertinent to the low immunogenicity of undifferentiated embryonic stem cells (ESCs) remain poorly understood. Here, we provide evidence that milk fat globule epidermal growth factor 8 (MFG-E8) is a vital mediator in this phenomenon and directly suppresses T cell immune responses. MFG-E8 is enriched in undifferentiated ESCs but diminished in differentiated ESCs.

Global Metabonomic and Proteomic Analysis of Human Conjunctival Epithelial Cells (IOBA-NHC) in Response to Hyperosmotic Stress.

"Dry eye" is a multifactorial inflammatory disease affecting the ocular surface. Tear hyperosmolarity in dry eye contributes to inflammation and cell damage. Recent research efforts on dry eye have been directed toward biomarker discovery for diagnosis, response to treatment, and disease mechanisms.

A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling.

The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self-renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self-renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two-layer regulatory circuit involving β-catenin, E-cadherin, PI3K/Akt, and Slug in a time-dependent manner. Short-term upregulation of β-catenin does not lead to the activation of T-cell factor (TCF)-eGFP Wnt reporter in hESCs.

Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential.

Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase.

p53 regulates neural stem cell proliferation and differentiation via BMP-Smad1 signaling and Id1.

Neural stem cells (NSCs) play essential roles in nervous system development and postnatal neuroregeneration and their deregulation underlies the development of neurodegenerative disorders. Yet how NSC proliferation and differentiation are controlled is not fully understood. Here we present evidence that tumor suppressor p53 regulates NSC proliferation and differentiation via the bone morphogenetic proteins (BMP)-Smad1 pathway and its target gene inhibitor of DNA binding 1 (Id1).

c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression.

Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion.

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response.

DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis.