Fondation MEDIC

www.fondation-medic.ch

Mechanisms that govern energy regulation in cancer stem cells (CSC)
[20.10.2016]
Project leader – Ivan Stamenkovic
Ivan Stamenkovic

Ivan Stamenkovic obtained his M.D. from the University of Geneva in 1978. Following full residencies in Internal Medicine and Pathology, he moved to Boston for a post-doctoral fellowship in the laboratory of Dr. Brian Seed in the Department of Molecular Biology at the Massachusetts General Hospital and the Department of Genetics at Harvard Medical School. In 1988, he was appointed Assistant Professor of Pathology at Harvard Medical School and in launched his own laboratory in the Department of Pathology at the Massachusetts General Hospital, with a joint appointment at the MGH Cancer Center. In 1992 he was appointed to Associate Professor of Pathology at HMS and Director of the Molecular Pathology Unit within the MGH Cancer Center. In 2001, he accepted a position as Professor of Experimental Pathology at the University of Lausanne. From 2007 to 2012 he functioned as Vice-Dean for research in the Faculty of Biology and Medicine at the University of Lausanne.

Division of Experimental Pathology
University Institute of Pathology
Rue du Bugnon 25
1011 Lausanne Switzerland

E-Mail: ivan.stamenkovic@chuv.ch

Group members
 

Luisa Cironi PhD

research associate

Sandrine Cornaz

graduate student

Cynthia Dayer

graduate student

Aurélie Formey PhD

post-doc

Giulia Fregni PhD

post-doc

Carlo Fusco PhD

research associate

Michalina Janiszewska PhD

post-doc

Marie-Aude Le Bitoux PhD

post-doc

Ruzanna Lehmann PhD

post-doc

Anne Planche

graduate student

Tanja Petricevic

graduate student

Project description
 

A growing number of malignancies are recognized to be composed of phenotypically heterogeneous cells that are hierarchically organized and have diverse degrees of differentiating and proliferative capacity. At the apex of the hierarchy are slowly cycling, undifferentiated cells that can self-renew, give rise to proliferating cell subpopulations and reconstitute a phenocopy of the primary tumour upon injection into immunocompromized mice – properties that have earned them the denomination of cancer stem cells (CSC). Despite being presumed to constitute the key cell subpopulation that determines tumor development, CSC are functionally defined based on no more than a handful of properties, including their ability to form spheres in vitro under serum-free conditions, initiate tumour formation in vivo and display higher resistance to conventional anticancer therapy than their non-spherogenic counterparts. Numerous key biological properties of these cells that may lead to a better understanding of their behaviour in addition to disclosing their potential therapeutic targetability have therefore yet to be elucidated. One of these properties is energy production.

Because CSC display plasticity that is typically associated with developing tissues, oncofetal proteins may participate in and potentially even determine many of their phenotypic and functional features. The oncofetal protein Imp2 is expressed in the developing mammalian brain and is required for normal embryonic development. Imp2 is an mRNA binding protein that plays an important role in subcellular mRNA localization, translation and stability. We have recently observed that IMP2 is highly expressed in glioblastoma (GBM) and Ewing’s sarcoma family tumors (ESFT), and our preliminary data suggest that IMP2 is implicated in energy production in CSC. We are currently addressing its possible functional role in GBM and ESFT CSC energy production and regulation.

Cancer cells display major bioenergetic differences from their normal counterparts. It is widely held that malignant cells rely on both oxidative phosphorylation (OXPHOS) and glycolysis to generate sufficient ATP for their metabolic requirements. Cancer cells are commonly found to have a high rate of glycolysis followed by lactic acid fermentation in the cytosol. Rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin, even in the presence of abundant oxygen (Warburg effect). Because glycolysis provides most of the energy required for cell proliferation, it has been suggested that cancer cells as well as normal proliferating cells may require activation of glycolysis in order to proliferate, whether oxygen is abundant or not. Despite the notion that tumors rely heavily on glycolysis for growth, recent work has revisited tumor cell bioenergetics and there is increasing evidence to suggest that OXPHOS plays an important role in transformation and tumor cell survival. Moreover, it is becoming clear that tumor cells can utilise both OXPHOS and glycolysis as a source of energy and that the choice of one versus the other depends on factors that include tumor size, stage, type of oncogene activation, and oxygen availability. Virtually nothing is currently known about mechanisms of energy generation by CSC. Given that CSC proliferate slowly, glycolysis may not be as critical as in more rapidly proliferating cells. Of note, recent work has shown that transformation of mesechymal stem cells (MSC) augments their dependence on OXPHOS for energy production.

Two tumors that are well suited for studying CSC properties are ESFT and GBM. ESFT are the second most common bone malignancy in children and young adults and are characterized by unique chromosomal translocations that give rise to fusion genes composed of EWS and an ets transcription factor family member. The fusion gene EWS-FLI-1 that arises as a result of the chromosomal translocation t(11;22)(q24;q12) is expressed in 85-90% of ESFT. The EWS-FLI-1 fusion protein provides the key oncogenic event in ESFT by inducing and repressing target genes that lead to transformation of permissive primary cells.

Glioblastomas (grade IV astrocytomas) are among the most malignant form of brain tumour with a survival time of approximately one year and notorious resistance to conventional anti-cancer therapy. Cells that fulfill the currently accepted functional CSC criteria have been isolated from ESFT and GBM based on their expression of diverse cell surface markers. These cells are amenable to examination of their energy requirements and mode of production. Our preliminary results indicate that IMP2 is implicated in regulating OXPHOS in cancer stem cells. Based on these initial observations, we are assessing the mechanism whereby IMP2 may regulate energy production in cancer stem cells and its potential as a therapeutic target.

Publications
 
2014 / 10.1158/0008-5472.CAN-14-1106
Cornaz-Buros S, Riggi N, DeVito C, Sarre A, Letovanec I, Provero P, Stamenkovic I. Targeting cancer stem-like cells as an approach to defeating cellular heterogeneity in Ewing sarcoma. Cancer Res. 2014 Nov 15;74(22):6610-22
» PubMed
2012 / 10.1016/j.ccr.2012.04.023
De Vito C, Riggi N, Cornaz S, Suvą ML, Baumer K, Provero P, Stamenkovic I. A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell. 2012 Jun 12;21(6):807-21
» PubMed
2012 / 10.1101/gad.188292.112
Janiszewska M, Suvą ML, Riggi N, Houtkooper RH, Auwerx J, Clément-Schatlo V, Radovanovic I, Rheinbay E, Provero P, Stamenkovic I. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. 2012 Sep 1;26(17):1926-44
» PubMed
2011 / 10.1586/era.10.235
Riggi N, Suvą ML, Stamenkovic I. The cancer stem cell paradigm in Ewing's sarcoma: what can we learn about these rare cells from a rare tumor?. Expert Rev Anticancer Ther. 2011 Feb;11(2):143-5
» PubMed
2011 / 10.1111/j.1600-0854.2011.01169.x
Bacac M, Fusco C, Planche A, Santodomingo J, Demaurex N, Leemann-Zakaryan R, Provero P, Stamenkovic I. Securin and separase modulate membrane traffic by affecting endosomal acidification. Traffic, 2011, 12:615-626
» PubMed
2011 / 10.1371/journal.pone.0023592
DeVito C, Riggi N, Suvą ML, Janiszewska M, Horlbeck J, Baumer K, Provero P, Stamenkovic I. Let-7a is a direct EWS-FLI-1 target implicated in Ewing’s sarcoma development. PLoSONE, 2011, 6:e23592
» PubMed
2011 / 10.1172/JCI41936
Mauti LA, Le-Bitoux MA, Baumer K, Stehle JC, Golshayan D, Provero P, Stamenkovic I. Myeloid derived suppressor cells are implicated in regulating tissue permissiveness for tumour metastasis during murine gestation. J. Clin Invest, 2011 121:2794-2807
» PubMed
2011 / 10.1371/journal.pone.0018640
Planche A, Bacac M, Provero P, Fusco C, Delorenzi M, Stehle JC, Stamenkovic I. Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS One. 2011;6(5):e18640
» PubMed
2010 / 10.1101/gad.1899710
Riggi N, Suvą ML, De Vito C, Provero P, Stehle JC, Baumer K, Cironi L, Janiszewska M, Petricevic T, Suvą D, Tercier S, Joseph JM, Guillou L, Stamenkovic I. EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes Dev. 2010, 24:916-932
» PubMed
2009 / 10.1158/0008-5472.CAN-09-1622
Suvą ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, Marquez VE, Clément V, Stamenkovic I. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009, 69:2911-2918
» PubMed
2009 / 10.1158/0008-5472.CAN-08-2242
Suvą ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, Suvą D, Clément V, Provero P, Cironi L, Osterheld MC, Guillou L, Stamenkovic I. Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res. 2009, 69:1776-1781
» PubMed