Molecular Oncology Research Institute

Boston, MA, United States

Molecular Oncology Research Institute

Boston, MA, United States
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Gupta P.B.,Cambridge Broad Institute | Gupta P.B.,Whitehead Institute For Biomedical Research | Fillmore C.M.,Tufts University | Jiang G.,Cambridge Broad Institute | And 7 more authors.
Cell | Year: 2011

Cancer cells within individual tumors often exist in distinct phenotypic states that differ in functional attributes. While cancer cell populations typically display distinctive equilibria in the proportion of cells in various states, the mechanisms by which this occurs are poorly understood. Here, we study the dynamics of phenotypic proportions in human breast cancer cell lines. We show that subpopulations of cells purified for a given phenotypic state return towards equilibrium proportions over time. These observations can be explained by a Markov model in which cells transition stochastically between states. A prediction of this model is that, given certain conditions, any subpopulation of cells will return to equilibrium phenotypic proportions over time. A second prediction is that breast cancer stem-like cells arise de novo from non-stem-like cells. These findings contribute to our understanding of cancer heterogeneity and reveal how stochasticity in single-cell behaviors promotes phenotypic equilibrium in populations of cancer cells. © 2011 Elsevier Inc.

Skibinski A.,Tufts University | Skibinski A.,Molecular Oncology Research Institute | Kuperwasser C.,Tufts University | Kuperwasser C.,Molecular Oncology Research Institute
Oncogene | Year: 2015

How breast diversity is generated is a fascinating and fundamental question with important clinical implications. It is clear that the diversity of phenotypes displayed by breast cancer cells reflects the array of cell types present in the disease-free breast epithelium, including luminal, basal and stem cells. Therefore, it is hypothesized that the molecular regulators governing normal development of the breast epithelium may double as engines of breast tumor diversity. In the past few years, a deepened understanding of the mammary epithelial hierarchy has prompted the search for the cellular precursors of breast tumors. At the same time, the use of novel experimental strategies including the new technology of massively parallel sequencing has provided insight into the origin and evolution of breast tumors. Here, we review the current understanding of the basis of the intrinsic subtypes and the sources of inter-tumor heterogeneity. © 2015 Macmillan Publishers Limited All rights reserved.

Tressel S.L.,Molecular Oncology Research Institute
Methods in molecular biology (Clifton, N.J.) | Year: 2011

G protein-coupled receptors (GPCR) are a superfamily of receptors that are vital in a wide array of physiological processes. Modulation of GPCR signaling has been an intensive area of therapeutic study, mainly due to the diverse pathophysiological significance of GPCRs. Pepducins are cell-penetrating lipidated peptides designed to target the intracellular loops of the GPCR of interest. Pepducins can function as agonists or antagonists of their cognate receptor, making them highly useful compounds for the study of GPCR signaling. Pepducins have been used to control platelet-dependent hemostasis and thrombosis, tumor growth, invasion, and angiogenesis, as well as to improve sepsis outcomes in mice. Pepducins have been successfully designed against a wide variety of GPCRs including the protease-activated receptors (PAR1, 2, 4), the chemokine receptors (CXCR1, 2, 4), the sphingosine-1-phosphate receptor (S1P3), the adrenergic receptor (ADRA1B), and have the potential to help reveal the functions of intractable GPCRs. Pharmacokinetic, pharmacodynamic, and biodistribution studies have showed that pepducins are widely distributed throughout the body except the brain and possess appropriate drug-like properties for use in vivo. Here, we discuss the delivery, pharmacology, and biodistribution of pepducins, as well as the effects of pepducins in models of inflammation, cardiovascular disease, cancer, and angiogenesis.

Banerjee P.,Tufts University | deJesus R.,Tufts University | Gjoerup O.,Molecular Oncology Research Institute | Schaffhausen B.S.,Tufts University
PLoS Pathogens | Year: 2013

Correct repair of damaged DNA is critical for genomic integrity. Deficiencies in DNA repair are linked with human cancer. Here we report a novel mechanism by which a virus manipulates DNA damage responses. Infection with murine polyomavirus sensitizes cells to DNA damage by UV and etoposide. Polyomavirus large T antigen (LT) alone is sufficient to sensitize cells 100 fold to UV and other kinds of DNA damage. This results in activated stress responses and apoptosis. Genetic analysis shows that LT sensitizes via the binding of its origin-binding domain (OBD) to the single-stranded DNA binding protein replication protein A (RPA). Overexpression of RPA protects cells expressing OBD from damage, and knockdown of RPA mimics the LT phenotype. LT prevents recruitment of RPA to nuclear foci after DNA damage. This leads to failure to recruit repair proteins such as Rad51 or Rad9, explaining why LT prevents repair of double strand DNA breaks by homologous recombination. A targeted intervention directed at RPA based on this viral mechanism could be useful in circumventing the resistance of cancer cells to therapy. © 2013 Banerjee et al.

Ahmed W.,Molecular Oncology Research Institute | Van Etten R.A.,Molecular Oncology Research Institute
Current Hematologic Malignancy Reports | Year: 2013

The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. © 2013 Springer Science+Business Media New York.

Corum D.G.,Medical University of South Carolina | Tsichlis P.N.,Molecular Oncology Research Institute | Muise-Helmericks R.C.,Medical University of South Carolina
FASEB Journal | Year: 2014

Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor γ coactivator-1 (PGC- 1α), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1α and to explore the effect on mitochondrial biogenesis and turnover during angiogenesis. Here we use standard biochemical analyses and Akt3-knockdown strategies to show that Akt3 controls the stabilization of chromosome maintenance region-1 (CRM-1), the major nuclear export receptor. Site-directed mutagenesis and association analyses show that PGC-1α nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1α target gene expression, compared to control levels. Akt3 inhibition causes autophagy, as measured by autophagosome formation, in a CRM-1-dependent, Akt1/ mTOR-independent pathway. In vivo, Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis compared to wild-type littermates (α5- and 2.5-fold decreases, respectively), as assessed by Matrigel plug assays. This correlates with an α1.5-fold decrease in mitochondrial Cox IV expression. Our studies suggest that Akt3 is a regulator of mitochondrial dynamics in the vasculature via regulation of CRM-1- dependent nuclear export.

Jun H.J.,Molecular Oncology Research Institute | Bronson R.T.,Harvard University | Charest A.,Molecular Oncology Research Institute | Charest A.,Tufts University
Stem Cells | Year: 2014

Glioblastoma multiforme (GBM) is the most lethal form of primary brain tumors, characterized by highly invasive and aggressive tumors that are resistant to all current therapeutic options. GBMs are highly heterogeneous in nature and contain a small but highly tumorigenic and selfrenewing population of stem or initiating cells (glioblastoma stem cells or GSCs). GSCs have been shown to contribute to tumor propagation and resistance to current therapeutic modalities. Recent studies of human GBMs have elucidated the genetic alterations common in these tumors, but much remains unknown about specific signaling pathways that regulate GSCs. Here we identify a distinct fraction of cells in a genetically engineered mouse model of EGFR-driven GBM that respond to anti-EGFR therapy by inducing high levels of c-MET expression. The MET-positive cells displayed clonogenic potential and long-term self-renewal ability in vitro and are capable of differentiating into multiple lineages. The MET-positive GBM cells are resistant to radiation and highly tumorigenic in vivo. Activation of MET signaling led to an increase in expression of the stemness transcriptional regulators Oct4, Nanog, and Klf4. Pharmacological inhibition of MET activity in GSCs prevented the activation of Oct4, Nanog, and Klf4 and potently abrogated stemness. Finally, the MET expressing cells were preferentially localized in perivascular regions of mouse tumors consistent with their function as GSCs. Together, our findings indicate that EGFR inhibition in GBM induces MET activation in GSCs, which is a functional requisite for GSCs activity and thus represents a promising therapeutic target. © AlphaMed Press 2013.

Kottakis F.,Molecular Oncology Research Institute | Polytarchou C.,Molecular Oncology Research Institute | Foltopoulou P.,Molecular Oncology Research Institute | Sanidas I.,Molecular Oncology Research Institute | And 2 more authors.
Molecular Cell | Year: 2011

The histone H3K27 methyltransferase EZH2 plays an important role in oncogenesis, by mechanisms that are incompletely understood. Here, we show that the JmjC domain histone H3 demethylase NDY1 synergizes with EZH2 to silence the EZH2 inhibitor miR-101. NDY1 and EZH2 repress miR-101 by binding its promoter in concert, via a process triggered by upregulation of NDY1. Whereas EZH2 binding depends on NDY1, the latter binds independently of EZH2. However, both are required to repress transcription. NDY1 and EZH2 acting in concert upregulate EZH2 and stabilize the repression of miR-101 and its outcome. NDY1 is induced by FGF-2 via CREB phosphorylation and activation, downstream of DYRK1A, and mediates the FGF-2 and EZH2 effects on cell proliferation, migration, and angiogenesis. The FGF-2-NDY1/EZH2-miR-101-EZH2 axis described here was found to be active in bladder cancer. These data delineate an oncogenic pathway that functionally links FGF-2 with EZH2 via NDY1 and miR-101. © 2011 Elsevier Inc.

Rudnick J.A.,Tufts University | Kuperwasser C.,Tufts University | Kuperwasser C.,Molecular Oncology Research Institute
Clinical and Experimental Metastasis | Year: 2012

Breast cancer is a heterogeneous, multi-factorial disease of aberrant breast development whose etiology relies upon several microenvironmental changes within the tissue. Within the last decade, it has become widely accepted that tumor cells frequently rely on signals from an activated microenvironment in order to proliferate and survive within a tissue. This activated tissue microenvironment involves the appearance of aSMA ? fibroblasts (referred to as "cancer associated fibroblasts"), the recruitment of various immune cells (macrophages, T cells, B cells, T regulatory cells), enhanced collagen I deposition, and epigenetic modifications of stromal cells. These stromal changes can predict patient survival and correlate with distinct breast tumor subtypes. Characterizing these stromal changes will facilitate their use as clinical biomarkers in breast cancer, and may facilitate their use as potential drug targets for adjuvant breast cancer therapy. © Springer Science+Business Media B.V. 2012.

Iliopoulos D.,Harvard University | Lindahl-Allen M.,Harvard University | Polytarchou C.,Molecular Oncology Research Institute | Hirsch H.A.,Harvard University | And 2 more authors.
Molecular Cell | Year: 2010

In an inducible oncogenesis model, the miR-200 family is inhibited during CSC formation but not transformation, and inhibition of miR-200b increases CSC formation. Interestingly, miR-200b directly targets Suz12, a subunit of a polycomb repressor complex (PRC2). Loss of miR-200 during CSC formation increases Suz12 expression, Suz12 binding, H3-K27 trimethylation, and Polycomb-mediated repression of the E-cadherin gene. miR-200b expression or Suz12 depletion blocks the formation and maintenance of mammospheres, and in combination with chemotherapy suppresses tumor growth and prolongs remission in mouse xenografts. Conversely, ectopic expression of Suz12 in transformed cells is sufficient to generate CSCs. The miR-200b-Suz12-cadherin pathway is important for CSC growth and invasive ability in genetically distinct breast cancer cells, and its transcriptional signature is observed in metastatic breast tumors. The interaction between miR-200 and Suz12 is highly conserved, suggesting that it represents an ancient regulatory mechanism to control the growth and function of stem cells. © 2010 Elsevier Inc.

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