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CELLULAR PLASTICITY AND CANCER GROUP

PRECLINICAL & TRANSLATIONAL RESEARCH
Cellular Plasticity and Cancer Group

MARÍA ABAD
Principal Investigator
Biosketch

Our group focuses on the interplay between cellular plasticity, stem cells and cancer. Cellular plasticity is recognized today as a critical feature of cancer cells that enables them to transit between different cellular states, including reversible transitions between mesenchymal and epithelial phenotypes, or stem cell-like and differentiated states. In tumors, the acquisition of stem cell properties correlates with increased malignancy and poor prognosis, and Cancer Stem Cells (CSCs) sustain the tumor bulk and contribute to treatment resistance and disease relapse post-therapy.

In this respect, we have reported that inducing dedifferentiation with the so-called Yamanaka factors can lead to the development of a variety of tumors. We have also demonstrated that tissue damage, as the main driver of cancer, triggers cell dedifferentiation and the acquisition of stem cell properties in vivo.

These observations have important therapeutic implications given that chemotherapy and radiotherapy – cornerstones for the treatment of most cancers – could have the side effect of inducing stemness in non-stem cancer cells and, in turn, possibly contribute to tumor recurrence and metastasis.

Our main objective is to better understand the mechanisms and players implicated in this process, with the ultimate goal of developing novel therapies based on the inhibition of cancer cell plasticity.

Recent findings have demonstrated that some genomic regions, previously considered as non-coding (including lncRNAs), contain small open reading frames encoding for evolutionary conserved, unannotated micropeptides. The few that have been identified to-date play key functions in elemental cellular processes, leading to a new level of complexity with major implications – from basic research to the clinical setting.

Over the past three years we have focused on identifying and characterizing novel cancer micropeptides that could represent novel actors in carcinogenesis.We have discovered six new cancer micropeptides and have obtained compelling evidence in vitro and in vivo that four of them act as novel tumor suppressors, inducing cell cycle arrest, differentiation or inhibition of mesenchymal traits in cancer cells.

The identification of tumor-micropeptides could be crucial in advancing insights into cancer physiopathology. Moreover, they could also serve as new cancer biomarkers for the early detection of disease and patient stratification for tailored therapies, as well as therapeutic targets.

In 2019, we have expanded our micropeptides studies and embarked on a new project that aims to identify novel secreted micropeptides that act as crucial cellular messengers for pancreatic cancer metastasis.

STRATEGIC GOALS

  • Advance understanding of the interplay between cellular plasticity and cancer.
  • Decipher the molecular mechanisms governing the acquisition of cellular plasticity during tumorigenesis.
  • Design novel therapeutic approaches based in the inhibition of cancer cell plasticity.

HIGHLIGHTS

  • We were awarded with the Health Research Grant 2018 from the ”la Caixa” Foundation.
  • We also received the Health Research Grant from La Mutua Madrileña Foundation.
  • María Abad was invited as a guest editor for the first ever special issue on small-ORF encoded microproteins published in Experimental Cell Research.
  • María Abad co-devised and launched the VHIO–”la Caixa” Scientific Seminars Seriesas Scientific Co-Chair alongside Laura Soucek (PI, Mouse Models of Cancer Therapies Group), and Elena Élez (Medical Oncologist and Clinical Investigator, Gastrointestinal & Endocrine Tumors Group).

 


TEAM

  • Principal Investigator
    • María Abad
  • Research Assistant
    • Marta Giménez
  • Postdoctoral Fellow
    • Elena Senís
  • PhD Students
    • Olga Boix
    • Alba Escriche
    • Emanuela Greco
    • Iñaki Merino
    • Marion Martínez
  • Visiting student
    • Camilla Bertani

Publications

  • Salazar-Roa M, Trakala M, Alvarez-Fernandez M, Valdes-Mora F, Munoz J, Zapatero-Solana E, Grana O, Peters T, Abad M, Bueno M, Gomez de Cedron M, Fernandez-Piqueras J, De Martino A, Serrano M, Wang D, Clark S, Ortega S and Malumbres M. Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells. In press. Embo Journal. DOI:10.15252/embj.2019104324
  • Merino I, Greco E, Abad M (2020). The microproteome of cancer: from invisibility to relevance. Experimental Cell Research. 2020;392(1):111997. doi:10.1016/j.yexcr.2020.111997
  • Senís E, Mosteiro L, Wilkening S, Wiedtke E, Nowrouzi A, Afzal S, Fronza R, Landerer H, Abad M, Niopek D, Schmidt M, Serrano M, Grimm D. AAVvector-mediated in vivo reprogramming into pluripotency. Nat Commun. 2018 Jul 9;9(1):2651. doi: 10.1038/s41467-018-05059-x.
  • Abad M, Hashimoto H, Zhou H, Morales MG, Chen B, Bassel-Duby R, Olson EN. Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity. Stem Cell Reports. 2017 Mar 14;8(3):548-560.
  • Marión RM, López de Silanes I, Mosteiro L, Gamache B, Abad M, Guerra C, Megías D, Serrano M, Blasco MA. Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis. Stem Cell Reports. 2017 Feb 14;8(2):460-475.
  • Gómez-Cabello D, Checa-Rodríguez C, Abad M, Serrano M, Huertas P. CtIP-Specific Roles during Cell Reprogramming Have Long-Term Consequences in the Survival and Fitness of Induced Pluripotent Stem Cells. Stem Cell Reports. 2017 Feb 14;8(2):432-445.
  • Mosteiro L, Pantoja C, Alcázar N, Marión RM, Chondronasiou D, Rovira M, Fernández-Marcos PJ, Muñoz M, Blanco-Aparicio C, Pastor J, Gómez-López G, de Martino A, Blasco MA, Abad M and Serrano M. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science. 2016 Nov 25;354(6315). pii: aaf4445.
  • Adrados I., Larrasa J., Galarreta A., López-Antona I., Menendez C., Abad M., Gil J., Moreno-Bueno G. And Palmero I. The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes. Oncogene. 2016 Jul 7;35(27):3485-94
  • Vilas JM, Ferreirós A, Carneiro C, Morey L, Da Silva-Álvarez S, Fernandes T, Abad M, Di Croce L, García-Caballero T, Serrano M, Rivas C, Vidal A, Collado M. Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins. Oncotarget. 2015 Feb 20;6(5):2992-3002.
  • Palla A.R., Piazzolla D., Abad M., Li H., Dominguez O., Schönthaler H.B., Wagner E.F. and Serrano M. Reprogramming activity of NANOGP8, a NANOG family member widely expressed in cancer. Oncogene. 2014 May 8;33(19):2513-9
  • Abad M, Mosteiro L, Pantoja C, Cañamero M, Rayon T, Ors I, Graña O, Megías D, Domínguez O, Martínez D, Manzanares M, Ortega S, Serrano M. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature. 2013 Oct 17;502(7471):340-5.
  • Abad M, Moreno A, Palacios A, Narita M, Blanco F, Moreno-Bueno G, Narita M and Palmero I. The tumor suppressor ING1 contributes to epigenetic control of cellular senescence. Aging Cell. 2011 Feb; 10:158-71.
  • Menéndez C, Abad M, Gómez-Cabello D, Moreno A and Palmero I. ING proteins in cellular senescence. Curr Drug Targets. 2009 May;10:406-1.
  • Abad M, Menéndez C, Fuchtabuer A, Serrano M, Fuchtbauer E-M and Palmero I. Ing1 mediates p53 accumulation and chromatin modification in response to oncogenic stress. J Biol Chem. 2007 Oct 19;282:31060-7
  • Goeman F.,Thormeyer D., Abad M., Serrano M., Schmidt  O., Palmero I. and Baniahmad A.  Growth inibition by the tumor suppressor p33ING1 in immortalized and primary cells: Involvement of two silencing domains and effect of Ras. Mol Cell Biol. 2005 Jan;25:422-31.