OncologyColorectal cancer laboratory

Unraveling Cancer Stem Cells and the Origins of Metastasis

Colorectal cancer laboratory
Group Leader

ICREA Research Professor, ERC Advanced Grant

+34 93 40 39008

Colorectal Cancer (CRC) is one of the leading causes of death by cancer worldwide. Most colorectal tumors develop as benign lesions but a small proportion progress to more malignant stages when the appropriate alterations in oncogenes and tumour suppressor genes occur. The final and deadliest step in colorectal cancer progression is the metastatic dissemination of colorectal cancer cells to other organs, mainly the liver.

Our lab studies the initiation of CRC and its progression from the early stages to the formation of aggressive tumors. We develop and examine cell and animal models that mimic this devastating disease. The ultimate goal is to obtain information that allows us to design new therapeutic and diagnostic tools.

1) Intestinal stem cells and CRC stem cells
Our studies address the identification, isolation and profiling of normal crypt stem cells and their malignant counterparts. We aim to identify the relationship between cell renewal in the intestinal epithelium and the initiation and progression of CRC.

2) EphB/ephrinB receptors in CRC
We recently demonstrated that the beta-catenin/Tcf target genes EphB2 and EphB3, two receptors of ephrinB ligands, suppress CRC progression beyond the early stages of tumor development. Most CRC silence the expression of EphB receptors around the adenoma-carcinoma transition, despite constitutive Wnt signalling. We are currently studying how EphB activity blocks tumor malignization as well as the mechanism of EphB down-regulation in advanced CRC.

Cancer

Early Colorectal Cancer lesions (dashed line) showing nuclear beta-catenin accumulation and expression of EphB2

3) The colonization of the liver by CRC cells
Liver metastasis is the main cause of death by colorectal cancer, yet the molecular mechanisms responsible for liver colonization by colorectal cancer cells remain largely unknown. We aim to identify the genes required by CRC cells to colonize the liver, with the focus on developing new therapeutic approaches to tackle the spread of CRC.

4) Molecular mechanisms that govern stem cell specification in normal epithelium and in CRC initiation
The intestinal epithelium is a prime example of cell renewal in adult tissues. The proliferative compartment of the intestinal epithelium is structured in millions of invaginations known as crypts of Lieberkühn. Each of these structures is a developmental unit that contributes to the complete renewal of the epithelium every few days throughout adulthood. Cell renewal in the intestinal epithelium is maintained by a small group of intestinal stem cells that reside at the bottom of each crypt. These stem cells slowly but continuously duplicate, giving rise to a transient population of progenitor cells that rapidly divide whilst migrating towards the intestinal lumen. In the mid-crypt region these cells stop dividing and differentiate. After 3-5 days, they are shed to the lumen and replaced by fresh descendants from the bottom of the crypts. Wnt signals are required for the maintenance of stem cells but also for the initiation of CRC. We study the similarities and differences in the molecular mechanisms responsible for the maintenance of stem cells and mutant stem cells in response to Wnt signals through the generation of animal models that mimic the initiation of the disease. These studies aim to identify molecular targets that may be used during early stages of the disease, and, in particular, in patients suffering from familial adenomatous polyposis (FAP).

5) Contribution of mutations in other signalling pathways to CRC progression
As CRC progresses, mutant cells accumulate alterations in other signalling pathways that modulate the initial progenitor phenotype imposed by mutations in Wnt signalling. Our research currently focuses on the contribution of TGF beta signalling to carcinogenesis through a multidisciplinary approach that includes gene expression profiling of tumour samples and the use of cell culture models and animal models in which TGF beta signalling is selectively induced or abolished in the intestinal tract.

Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D, Cortina C, Morral C, Barceló C, Tosi S, Riera A, Attolini CS, Rossell D, Sancho E and Batlle E.
Nat Genet, 47 (4), 320-329 (2015)
Oskarsson T, Batlle E and Massagué J.
Cell Stem Cell, 14 (3), 306-21 (2014)
Whissell G, Montagni E, Martinelli P, Hernando-Momblona X, Sevillano M, Jung P, Cortina C, Calon A, Abuli A, Castells A, Castellvi-Bel S, Nacht AS, Sancho E, Stephan-Otto Attolini C, Vicent GP, Real FX and Batlle E.
Nat Cell Biol, 16 (7), 695-707 (2014)
Urosevic J, Garcia-Albéniz X, Planet E, Real S, Céspedes MV, Guiu M, Fernandez E, Bellmunt A, Gawrzak S, Pavlovic M, Mangues R, Dolado I, Barriga FM, Nadal C, Kemeny N, Batlle E, Nebreda AR and Gomis RR.
Nat Cell Biol, 16 (7), 685-94 (2014)
Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D, Mangues R, Massagué J, Sancho E and Batlle E.
Cancer Cell, 22 (5), 571-84 (2012)
Campbell K, Whissell G, Franch-Marro X, Batlle E and Casanova J.
Dev Cell, 21 (6), 1051-61 (2011)
Jung P, Sato T, Merlos-Suárez A, Barriga FM, Iglesias M, Rossell D, Auer H, Gallardo M, Blasco MA, Sancho E, Clevers H and Batlle E.
Nat Med, 17 (10), 1225-7 (2011)
Solanas G, Cortina C, Sevillano M and Batlle E.
Nat Cell Biol, 13 (9), 1100-7 (2011)
Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Muñoz P, Clevers H, Sancho E, Mangues R and Batlle E.
Cell Stem Cell, 8 (5), 511-24 (2011)

This group receives financial support from the following sources:

  • Ministerio de Educación y Ciencia (Spanish Ministry of Science and Education)
  • Generalitat de Catalunya (DURSI) (Government of Catalonia) 
  • SuppresSTEM consortium
  • Ministerio de Economía y Competitividad (MINECO)
  • European Commission (EC), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa"

     

People

Group news & mentions

<p>Eduard Batlle, Carmen and Severo Ochoa Prize 2016</p>
15 Nov 2016

Coordinator of the Oncology Programme at the Institute for Research in Biomedicine (IRB Barcelona) and ICREA research professor

10 Oct 2016

On 13 and 14 October, on the occasion of a B·Debate, an initiative promoted by Biocat and Obra Social “la Caixa”, national and international experts in epigenetics and cancer will come together for

30 Sep 2016

Eduard Batlle’s work on colon cancer and Patrick Aloy’s on the network biology  of Alzheimer’s disease feature among the newspaper El Mundo’s list of the most prom

<p>34 researchers have been awarded in the 2016 edition. Today, all the attendees at the ceremony in the AECC institutional act held in Barcelona (Picture: AECC)</p>
22 Sep 2016

Today, Jelena Urosevic and Carles Barceló, postdoctoral fellows at the Institute for Research in Biomedicine (IRB Barcelona), will officially be presented with funding over 5 years

Upcoming events

12 Dec
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
Marek Mlodzik, The Icahn School of Medicine at Mount Sinai, NY
13 Dec
Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
Neus Prats, Core Facility Manager and Mònica Aguilera, Research Officer
14 Dec
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
María Gómez Vicentefranqueira (Centre Biología Molecular Severo Ochoa, Madrid)