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CHROMATIN DYNAMICS IN CANCER GROUP

PRECLINICAL & TRANSLATIONAL RESEARCH
Chromatin Dynamics in Cancer Group

SANDRA PEIRÓ
Principal Investigator
Biosketch

Our laboratory seeks to better understand how epigenetics and chromatin structure and dynamics affect cell behavior, with a specific focus on cancer. Through our comprehensive studies, we aim to dissect the role of epigenetic changes in cancer, identify mechanisms of response and resistance to anti-cancer medicines, and explore new therapeutic opportunities.

Over the last few years, we have elucidated epigenetic changes during EMT and cancer progression, and discovered a new histone H3 modification (oxidized H3) enriched in heterochromatin that is implicated in chromatin condensation and the transition to a metastatic cell fate (published in Mol. Cell, FEBS J., and Oncogene). We have also discovered an important role for lamin B1 in the reorganization of 3D chromatin structure during EMT (published 2018, Nat. Commun.).

We are equally committed to describing the association of chromatin conformation modifications with the acquisition of malignant traits and evaluating the functional consequences of these developments in genes and pathways. Next steps will involve deciphering how these alterations occur at the molecular level and more precisely identifying these putative culprits for future targeted therapy.

STRATEGIC GOALS

  • The laboratory has two main goals:
    • To understand the 3D chromatin structure and dynamics in cancer from a basic research perspective.
    • Identify biomarkers and epigenetic mechanisms of drug response and resistance in ER+ breast cancer, cholangiocarcinomas, and NUT-midline carcinomas.

    Specifically:

    • Which molecular events direct chromatin movements?
    • Are these events due to the specific binding of a subset of transcription factors?
    • To what extent are chromatin architecture changes reversible?
    • During the process of metastasis cells go through an intermediate state. Does this state possess a specific and genomic architecture that determines the metastatic fate? Could we block this ?
    • What is the role of oxidized H3 in other tumor types? Could we inhibit this oxidation using a peptide-based therapy?
    • Identification of key epigenetic components using PDXs, Cas9–cholangiocarinoma cell lines, and organoids with epigenetic drugs currently used in clinical trials.
    • Can we combine different drugs to overcome resistance?
    • Which are the biomarkers that will enable us to stratify patients for more effective treatments?

HIGHLIGHTS

  • We have discovered the molecular function of oxidize Histone H3 in TNBC.
  • We have consolidated our collaboration with VHIO’s Gastrointestinal & Endocrine Tumors Group (PI: Teresa Macarulla) through a grant received from La Marató TV3
  • Gemma Serra obtained her PhD from the Pompeu Fabra University, Barcelona, with magna cum laude.

 


TEAM

  • Principal Investigator
    • Sandra Peiró
  • Post-Doctoral Fellow
    • Laura Pascual
    • Tian Tian
    • Gemma Serra
  • Graduate Students
    • Marc Cosin
    • Carmen Escudero
    • Queralt Serra
  • Students
    • Josep Francesch
    • Laura Mondejar
    • Macarena Palacios
  •  Technician
    • Jessica Querol Paños

Most relevant scientific publications

  • Pascual-Reguant L, Blanco E, Galan S, Le Dily F, Cuartero Y, Serra-Bardenys G, Di Carlo V, Iturbide A, Cebrià-Costa JP, Nonell L, de Herreros AG, Di Croce L, Marti-Renom MA, Peiró S. Lamin B1 mapping reveals the existence of dynamic and functional eurchromatin lamin B1 domains. Nat Commun. 2018 Aug 24;9(1):3420.
  • Verde G, De Llobet LI, Wright RHG, Quilez J, Peiró S, Le Dily F, Beato M. Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells. Cancers (Basel). 2018 Oct 5;10(10).
  • Mazzolini R, Gonzalez N, Garcia-Garijo A, Millanes-Romero A, Peiró S, Smith S, Garcia de Herreros A and Canudas S. Snail1 transcription factor controls telomere transcription and integrity. Nucleic Acids Res. 2017 Oct 20.
  • Izquierdo-Bouldstridge A, Bustillos A, Bonet-Costa C, Aribau-Miralbés P, l García-Gomis D, Dabad M, Esteve-Codina A, Pascual-Reguant L, Peiró S, Esteller M, Murtha M, Millán-Ariño L, Jordan A. Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Res. 2017 Nov 16;45(20):11622-11642.
  • Verde G, Querol-Paños J, Cebrià-Costa JP, Pascual-Regu ant L, Serra-Bardenys G, Iturbide A and Peiró S. Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis. Epigenomes. 2017, 1(1), 4.
  • Herranz N, Dave N, Millanes-Romero A, Pascual L, Morey L, Díaz VM, Lorenz-Fonfria V, Gutierrez-Gallego R, Jerónimo C, Itubide A, Di Croce L, García de Herreros A and Peiró S. Lysyl Oxidase-Like 2 (LOXL2) Oxidizes Trimethylated Lysine 4 in Histone H3. FEBS J. 2016
  • Itubide A, Pascual L, Fargas L, Cebrià JP, Alsina B, García de Herreros A and Peiró S. LOXL2 oxidizes methylated TAF10 and controls TFIID-dependent genes during neural progenitor differentiation. Mol Cell. 2015
  • Millanes-Romero A, Herranz  N,  Loubat  J,  Iturbide  A,  Perrera  V,  Gil  J,  Jenuwein  T,  García  de Herreros A and Peiró S. Regulation of Heterochromatin Transcription by Snail1/ LOXL2 During Epithelial to Mesenchymal Transition. Mol Cell. 2013.
  • Herranz N, Pasini D, Díaz V, Francí C, Gutierrez  A, Dave N, Escrivà M, Hernandez-Muñoz  I, di Croce  L,  Helin  K,  García  de  Herreros  A  and  Peiró  S.  Polycomb complex 2 is required for E- Cadherin repression by Snail1 transcription factor. Mol Cell Biol. 28: 47772-81. 2008.
  • Escrivà M*, Peiró S* (co-authors),  Herranz N, Villagrasa P, Dave N, Montserrat-Sentís  B, Murray SA, Francí C, Gridley T, Virtanen I and García de Herreros A. Repression of PTEN phosphatase by Snail1  transcriptional  factor  during  gamma  radiation-induced  apoptosis. Mol Cell Biol. 28: 1528-40. 2008.

All publications

  • Mazzolini R, Gonzalez N, Garcia-Garijo A, Millanes-Romero A, Peiró S, Smith S, Garcia de Herreros A and Canudas S. Snail1 transcription factor controls telomere transcription and integrity. Nucleic Acids Res. 2017 Oct 20.
  • Izquierdo-Bouldstridge A, Bustillos A, Bonet-Costa C, Aribau-Miralbés P, l García-Gomis D, Dabad M, Esteve-Codina A, Pascual-Reguant L, Peiró S, Esteller M, Murtha M, Millán-Ariño L, Jordan A. Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Res. 2017 Nov 16;45(20):11622-11642.
  • Verde G, Querol-Paños J, Cebrià-Costa JP, Pascual-Regu ant L, Serra-Bardenys G, Iturbide A and Peiró S. Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis. Epigenomes. 2017, 1(1), 4.
  • Herranz N, Dave N, Millanes-Romero A, Pascual L, Morey L, Díaz VM, Lorenz-Fonfria V, Gutierrez-Gallego R, Jerónimo C, Itubide A, Di Croce L, García de Herreros A and Peiró S. Lysyl Oxidase-Like 2 (LOXL2) Oxidizes Trimethylated Lysine 4 in Histone H3. FEBS J. 2016
  • Frigola J, Iturbide A, Lopez-Bigas N, Peiró S and Gonzalez-Pérez A. Altered oncomodules underline chromatin regulatory factors driver mutations. Oncotarget.  2016.
  • Beltran M, Aparicio-Prat E, Mazzolini R, Millanes-Romero A, Massó P, Jenner R, Díaz V, Peiró S and Garcia de Herreros A. Splicing of a non-coding antisense transcript controls LEF1 gene expression. Nucl Acids Res. 2015
  • Itubide A, Pascual L, Fargas L, Cebrià JP, Alsina B, García de Herreros A and Peiró S. LOXL2 oxidizes methylated TAF10 and controls TFIID-dependent genes during neural progenitor differentiation. Mol Cell. 2015
  • Itubide A, García de Herreros A and Peiró S. A new role for LOX and LOXL2 proteins in transcription regulation. FEBS Lett. Upcoming Special Issue: Epigenetics. 2014
  • Cebrià JP, Millanes-Romero A, García de Herreros A and Peiró S. The Essential Role of Heterochromatin Transcription in Cellular Transitions: The Epithelial-to-Mesenchymal Transition (EMT), a Particular Case. Mol Cell Oncol. 2014.
  • Millanes-Romero A, Herranz  N,  Loubat  J,  Iturbide  A,  Perrera  V,  Gil  J,  Jenuwein  T, García  de Herreros A and Peiró S. Regulation of Heterochromatin Transcription by Snail1/ LOXL2 During Epithelial to Mesenchymal Transition. Mol Cell. 2013.
  • Villagrasa P, Díaz VM, Viñas-Castells R, Peiró S, Del Valle-Pérez B, Dave N, Rodríguez-Asiain  A, Casal JI, Lizcano JM, Duñach M, García de Herreros A. Akt2 interacts with Snail1 in the E-Cadherin promoter. Oncogene. 2011.
  • Dave N, Guaita-Esteruelas  S, Gutarra S, Frias À, Beltran M, Peiró S, de Herreros AG. Functional cooperation between Snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. J Biol Chem. 2011.
  • Garcia  de  Herreros  A,  Peiró  S,  Nassour  M,  Savagner  P.  Snail  family  regulation  and  epithelial mesenchymal transitions in breast cancer progression. J. Mammary Gland Biol Neoplasia. 2010.
  • Herranz N, Pasini D, Díaz V, Francí C, Gutierrez  A, Dave N, Escrivà M, Hernandez-Muñoz  I, di Croce  L,  Helin  K,  García  de  Herreros  A  and  Peiró  S.  Polycomb  complex  2  is  required  for  E- Cadherin repression by Snail1 transcription  factor. Mol Cell Biol. 28: 47772-81. 2008.
  • Escrivà M*, Peiró S* (co-authors),  Herranz N, Villagrasa P, Dave N, Montserrat-Sentís  B, Murray SA, Francí C, Gridley T, Virtanen I and García de Herreros A. Repression of PTEN phosphatase by Snail1  transcriptional  factor  during  gamma  radiation-induced  apoptosis. Mol Cell Biol. 28: 1528-40. 2008.
  • Mejias-Luque  R,  Peiró  S,  Vincent  A,  Van  Seuningen  I  and  de  Bolós  C.  IL-6  induces  MUC4 expression  through  go130/STAT3   pathway  in  gastric  cancer  cell  lines.  BBA  Mol Cell Res. 10: 1728-36. 2008.
  • Solanes G, Porta de la Riva M, Agustí C, Casagolda  D, Sanchez-Aguilera  F, Larriba MJ, Pons F, Peiró S, Escrivà M, Muñoz A, Duñach M, García de Herreros A and Baulida J. E-Cadherin controls b-catenin  and  NFkB  transcriptional  activity  in  mesenchymal  gene  expression. J Cell Sci. 121: 2224-34. 2008.
  • Wanami  L, Chen  H, Peiró  S, García  de Herreros  A and Bacheler R. Vascular  endothelial  growth factor-A stimulates Snail expression in breast tumor cells: Implications for tumor progression. Exp Cell Res. 13: 2448-53. 2008.
  • Ortiz-Zapater  E*, Peiró S* (co-authors),  Roda O, Coromines  JM, Aguilar S, Ampurdanes C, Real FX  and  Navarro  P. Tissue  plasminogen  activator  induces  pancreatic  cell proliferation  by  a non- catalytic mechanism that requires ERK1/2 activation through Epidermal Growth Factor receptor and Annexin A2. Am J Pathol. 170: 1573-84. 2007.
  • Peiró S, Escrivà M, Puig I, Barberà MJ, Dave N, Herranz N, Larriba MJ, Takkunen M, Francí C, Muñoz A, Virtanen I, Baulida J and García de Herreros A. Snail1 transcriptional  repressor binds to its own promoter and controls its expression. Nucl Acids Res. 34: 2077-84. 2006.
  • Palmer HG, Larriba MJ, Garicia JM, Ordoñez-Moran  P, Pena C, Peiró S, Puig I, Rodriguez De la Fuente  R, Bernad  A, Pollan  M, Bonilla  F, Gamallo  C, García  de Herreros  A and Muñoz  A. The transcription  factor  Snail1  represses  vitamin  D receptor expression  and responsiveness  in human colon cáncer. Nat Med. 10: 917-19. 2004.
  • Barberà MJ, Dominguez D, Puig I, Julien-Grille S, Guaita S, Baulida J, Francí C, Peiró S, Deehar S, Laure L and García de Herreros A. Regulation of Snail transcription during epitelial to mesenchymal transition of tumor cells. Oncogene. 23: 7345-54. 2004.
  • Iularu M, Demontis F, Corada M, Zanetta L, Drake C, Gariboldi M, Peiró S, Cano A, Navarro P, Cattelino A, Tognin S, Marchisio PC and Dejana E. VE-Cadherin expression and clustering maintain low levels of surviving in endothelial cells. Am J Pathol. 165: 181-9. 2004.
  • Llovera M, de Pablo Y, Egea J, Encinas M, Peiró S, Martín-Zanca D, Rocamora N and Comella JX. Trk is a calmodulin-binding protein: Implications for receptor processing.  J Neurochem. 88: 422. 2004