334 results match your criteria heterogeneity notch


FGF-MAPK signaling regulates human deep-layer corticogenesis.

Stem Cell Reports 2021 Mar 30. Epub 2021 Mar 30.

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia.

Despite heterogeneity across the six layers of the mammalian cortex, all excitatory neurons are generated from a single founder population of neuroepithelial stem cells. However, how these progenitors alter their layer competence over time remains unknown. Here, we used human embryonic stem cell-derived cortical progenitors to examine the role of fibroblast growth factor (FGF) and Notch signaling in influencing cell fate, assessing their impact on progenitor phenotype, cell-cycle kinetics, and layer specificity. Read More

View Article and Full-Text PDF

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Center for Theoretical Biological Physics and Departments of Physics and Bioengineering, Northeastern University, Boston, MA 02115, USA.

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. Read More

View Article and Full-Text PDF

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic.

Front Cell Dev Biol 2021 8;9:640587. Epub 2021 Mar 8.

Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.

Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Read More

View Article and Full-Text PDF

Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling.

Neurosci Lett 2021 04 8;750:135802. Epub 2021 Mar 8.

Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India.

In view of inconsistencies in the association studies of alpha synuclein (SNCA) rs7684318 (chr4: 90655003 T > C) with Parkinson's disease (PD), we conducted a meta-analysis to establish the association of this variant with PD and examined changes in transcription factor binding. SNCA rs7684318 C-allele was identified as genetic risk factor for PD in fixed (OR: 1.53, 95 % CI: 1. Read More

View Article and Full-Text PDF

New Insights into the Molecular Profile of Penile Squamous Cell Carcinoma.

Clin Cancer Res 2021 Mar 2. Epub 2021 Mar 2.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Genomic alterations in penile squamous cell carcinoma (PSCC) appear similar to squamous cell carcinomas of the head and neck and esophagus but not lung, skin, bladder, and cervix. PSCCs display genomic heterogeneity, low mutation burden, and potentially actionable alterations in the Notch, DNA repair, kinase, and cell-cycle pathways.. Read More

View Article and Full-Text PDF

Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-genetic Heterogeneity in Prostate Cancer Cells.

Entropy (Basel) 2021 Feb 26;23(3). Epub 2021 Feb 26.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial-mesenchymal transition (EMT), and c) Notch-Delta-Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Read More

View Article and Full-Text PDF
February 2021

In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8 T cell fate decisions.

Cell 2021 Mar 25;184(5):1245-1261.e21. Epub 2021 Feb 25.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

How early events in effector T cell (T) subsets tune memory T cell (T) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of T and T cells using in vivo pooled CRISPR screening, focusing on negative regulators of T responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of T differentiation, in part through modulating mTORC1 signaling. Read More

View Article and Full-Text PDF

Innate immune evasion revealed in a colorectal zebrafish xenograft model.

Nat Commun 2021 02 19;12(1):1156. Epub 2021 Feb 19.

Champalimaud Centre for the Unknown, Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.

Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system. Herein, we explore the fast zebrafish xenograft model to investigate the innate immune contribution to this process. Using multiple breast and colorectal cancer cell lines and zAvatars, we find that some are cleared (regressors) while others engraft (progressors) in zebrafish xenografts. Read More

View Article and Full-Text PDF
February 2021

The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China.

Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). Read More

View Article and Full-Text PDF
January 2021

Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma.

Cancers (Basel) 2021 Jan 10;13(2). Epub 2021 Jan 10.

Department of Pathology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.

High grade colorectal carcinomas (HG-CRCs), which comprise 15% of colorectal carcinomas, are underrepresented in reported molecular studies. Clinicopathological, immunohistochemical, and molecular features of 40 HG-CRCs are described. Moreover, glandular and solid areas of 25 tumors were separately analyzed. Read More

View Article and Full-Text PDF
January 2021

Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.

J Biol Chem 2020 Dec 3:100121. Epub 2020 Dec 3.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China;. Electronic address:

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Read More

View Article and Full-Text PDF
December 2020

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis.

Cells 2021 Jan 7;10(1). Epub 2021 Jan 7.

Department of Biochemistry and Molecular Biology, Medical University in Lublin, ul. Chodzki 1, 20-093 Lublin, Poland.

The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Read More

View Article and Full-Text PDF
January 2021

Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis.

Front Cell Dev Biol 2020 15;8:592616. Epub 2020 Dec 15.

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland.

The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. Read More

View Article and Full-Text PDF
December 2020

Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas.

Haematologica 2020 12 3;Online ahead of print. Epub 2020 Dec 3.

Division of Hematopathology.

Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those with HIV infection and solid organ allograft recipients. Most prior studies have focused on delineating the clinicopathologic features and genetic attributes of HIV-related PBLs, where MYC deregulation and EBV infection, and more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBLs is not well characterized and data on underlying genetic alterations are limited. Read More

View Article and Full-Text PDF
December 2020

Precise T cell recognition programs designed by transcriptionally linking multiple receptors.

Science 2020 11;370(6520):1099-1104

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by using synthetic Notch receptors to transcriptionally interconnect multiple molecular recognition events. These synthetic circuits allow engineered T cells to integrate extra- and intracellular antigen recognition, are robust to heterogeneity, and achieve precise recognition by integrating up to three different antigens with positive or negative logic. Read More

View Article and Full-Text PDF
November 2020

Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.

J Biol Chem 2020 Nov 24. Epub 2020 Nov 24.

School of Life Sciences, Xiamen University, China.

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Read More

View Article and Full-Text PDF
November 2020

Pharmacological Prevention of Noise-induced Hearing Loss: A Systematic Review.

Otol Neurotol 2021 Jan;42(1):2-9

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina.

Objective: This study aims to explore and determine the effectiveness of current pharmacologic agents for the prevention of noise-induced hearing loss (NIHL) via a systematic review.

Databases Reviewed: The PubMed, Scopus, ClinicalTrials.gov, and Cochrane Library databases were searched from inception through February 6, 2020. Read More

View Article and Full-Text PDF
January 2021

Single cell RNA-seq reveals developmental plasticity with coexisting oncogenic and immune evasion programs in ETP-ALL.

Blood 2020 Nov 23. Epub 2020 Nov 23.

Boston Children's Hospital, United States.

Lineage plasticity and stemness have been invoked as the cause of therapy resistance in cancer, as these flexible states allow cancer cells to de-differentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed / refractory early T-cell progenitor acute lymphoblastic leukemia carrying activating NOTCH1 mutations, by full-length single cell RNA sequencing of malignant and microenvironmental cells. We identified two highly distinct stem-like states that critically differ in their cell-cycle and oncogenic signaling. Read More

View Article and Full-Text PDF
November 2020

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers.

Mol Cell 2020 11;80(4):562-577

Pathology and Laboratory Medicine and Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA.

Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. Read More

View Article and Full-Text PDF
November 2020

Tension heterogeneity directs form and fate to pattern the myocardial wall.

Nature 2020 12 18;588(7836):130-134. Epub 2020 Nov 18.

Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

How diverse cell fates and complex forms emerge and feed back to each other to sculpt functional organs remains unclear. In the developing heart, the myocardium transitions from a simple epithelium to an intricate tissue that consists of distinct layers: the outer compact and inner trabecular layers. Defects in this process, which is known as cardiac trabeculation, cause cardiomyopathies and embryonic lethality, yet how tissue symmetry is broken to specify trabecular cardiomyocytes is unknown. Read More

View Article and Full-Text PDF
December 2020

Specific decreasing of Na channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.

Sci Rep 2020 11 17;10(1):19964. Epub 2020 Nov 17.

Department of Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Japan.

Reduced cardiac sodium (Na) channel current (I) resulting from the loss-of-function of Na channel is a major cause of lethal arrhythmias in Brugada syndrome (BrS). Inspired by previous experimental studies which showed that in heart diseases I was reduced along with expression changes in Na channel within myocytes, we hypothesized that the local decrease in I caused by the alteration in Na channel expression in myocytes leads to the occurrence of phase-2 reentry, the major triggering mechanism of lethal arrhythmias in BrS. We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na channel expression changes in each myocyte cause the phase-2 reentry in BrS. Read More

View Article and Full-Text PDF
November 2020

Monitoring of Active Notch Signaling in Mouse Bladder Urothelium.

Methods Mol Biol 2020 Nov 15. Epub 2020 Nov 15.

Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

Notch signaling plays a crucial role in differentiation and homeostasis in a wide variety of epithelia. The tumor suppressor role of Notch in bladder urothelium is well accepted as the inactivation of this pathway due to damaging mutations in its components is associated with neoplastic transformation. Monitoring Notch signaling is therefore critical to understand how the deregulation of cell-cell communication can lead to differentiation loss and carcinogenesis. Read More

View Article and Full-Text PDF
November 2020

Mitigating Scatter in Mechanical Properties in AISI 410 Fabricated via Arc-Based Additive Manufacturing Process.

Materials (Basel) 2020 Oct 29;13(21). Epub 2020 Oct 29.

Lincoln Electric Company, Cleveland, OH 44117, USA.

Wire-based metal additive manufacturing utilizes the ability of additive manufacturing to fabricate complex geometries with high deposition rates (above 7 kg/h), thus finding applications in the fabrication of large-scale components, such as stamping dies. Traditionally, the workhorse materials for stamping dies have been martensitic steels. However, the complex thermal gyrations induced during additive manufacturing can cause the evolution of an inhomogeneous microstructure, which leads to a significant scatter in the mechanical properties, especially the toughness. Read More

View Article and Full-Text PDF
October 2020

Hedgehog Signaling Regulates Neurogenesis in the Larval and Adult Zebrafish Hypothalamus.

eNeuro 2020 Nov-Dec;7(6). Epub 2020 Oct 26.

Department of Biology, University of Massachusetts, Amherst, 01003 MA.

Neurogenesis is now known to play a role in adult hypothalamic function, yet the cell-cell mechanisms regulating this neurogenesis remain poorly understood. Here, we show that Hedgehog (Hh)/Gli signaling positively regulates hypothalamic neurogenesis in both larval and adult zebrafish and is necessary and sufficient for normal hypothalamic proliferation rates. Hh-responsive radial glia represent a relatively highly proliferative precursor population that gives rise to dopaminergic, serotonergic, and GABAergic neurons. Read More

View Article and Full-Text PDF
October 2020

Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer.

Transl Oncol 2021 Jan 14;14(1):100891. Epub 2020 Oct 14.

College of Bioscience and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110866, China; College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning 110866, China. Electronic address:

Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to α-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Read More

View Article and Full-Text PDF
January 2021

Notch in Head and Neck Cancer.

Adv Exp Med Biol 2021 ;1287:81-103

Institute of Oral Biology, Orofacial Development and Regeneration, University of Zurich, Zurich, Switzerland.

Head and neck cancer is a group of neoplastic diseases affecting the facial, oral, and neck region. It is one of the most common cancers worldwide with an aggressive, invasive evolution. Due to the heterogeneity of the tissues affected, it is particularly challenging to study the molecular mechanisms at the basis of these tumors, and to date we are still lacking accurate targets for prevention and therapy. Read More

View Article and Full-Text PDF
October 2020

Induction and transmission of oncogene-induced senescence.

Cell Mol Life Sci 2021 Feb 16;78(3):843-852. Epub 2020 Sep 16.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.

Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. Read More

View Article and Full-Text PDF
February 2021

Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia.

Blood Cancer Discov 2020 Sep;1(2):178-197

Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI.

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Read More

View Article and Full-Text PDF
September 2020

Noncystic cerebellopontine angle hemangioblastoma: A case of an atypical location.

Int J Surg Case Rep 2020 29;74:234-237. Epub 2020 Aug 29.

Department of Medicine, Universidade Federal de Sergipe, Aracaju, Brazil; Division of Neurosurgery, Fundação de Beneficência Hospital de Cirurgia, Aracaju, Brazil. Electronic address:

Introduction: Extra-axial cerebellopontine angle (CPA) hemangioblastoma is a rare condition in which the correct differential diagnosis from other CPA lesions can affect the best treatment choice. These are benign tumors that are highly vascularized and mostly present in the cystic form. About twenty-six cases have been reported in the literature with this same location and with a noncystic aspect. Read More

View Article and Full-Text PDF

Identification of miRNA-mRNA Network in Autism Spectrum Disorder Using a Bioinformatics Method.

J Mol Neurosci 2021 Apr 2;71(4):761-766. Epub 2020 Sep 2.

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Autism spectrum disorder (ASD) includes a heterogeneous group of disorders with different contributing genetics and epigenetics factors. Aberrant expression of miRNAs has been detected in ASD children compared with normally developed children. Due to the heterogeneity of this disorder, there is no consensus on ASD-associated miRNAs; thus, it is necessary to develop a model for comprehensive assessment of the role of miRNAs in ASD. Read More

View Article and Full-Text PDF