Research

About

The Cancer Genetics and Epigenetics group studies alterations that impact the development of colorectal cancer (CRC) and gastric cancer, as well as their corresponding tumour phenotypes.

Their studies have extensively investigated DNA hypomethylation of genes and repetitive elements in the very early steps of gastrointestinal carcinogenesis, identifying that aberrant genomic demethylation of the mucosa is a risk factor for gastric and colorectal cancer development. They have also found that hypomethylation of some specific repetitive DNA elements is associated with aberrant genome duplication, which is known to promote chromosomal instability and contribute to the development of gastrointestinal cancers.

The current research of the group aims to explore the molecular mechanisms underlying this association between hypomethylation of those repetitive DNA elements and aberrant genomic duplication, which could reveal fundamental factors in the early stages of tumorigenesis preceding malignant transformation.

The group is also studying epigenetic alterations associated with CRC immunogenicity. Their recent studies have revealed the association between the epigenetic silencing of genes encoding extracellular matrix remodelers and higher lymphocytic infiltration levels in non-hypermutant CRCs. Pharmacological inhibition of these extracellular matrix remodelers could increase tumour immunogenicity, resulting in more abundant lymphocytic infiltration and enhanced response to immune checkpoint inhibitor therapy. This research builds on the group's long-standing interest in DNA methylation alterations affecting extracellular matrix remodelers, which led to the discovery of frequent and coordinated hypermethylation of ADAMTS genes. Additionally, their research has identified methylation alterations in other genes that have a substantial impact on CRC phenotype, they developed microarray-based technologies to analyse genomic methylation and discovered highly specific and sensitive epigenetic biomarkers for biliary cancer detection.

In their research, the CGE team employs an interdisciplinary approach that combines epigenomics, transcriptomics, and genomics, computational analysis, molecular biology, and cell biology. Over the past few years, the group has been actively developing novel, cost-efficient, and scalable in vitro immuno-oncology models for genetic and pharmacological studies aimed at enhancing tumour immunogenicity and improving the response of gastrointestinal cancers to the most recently developed immunotherapies.

Keywords: Epigenomics, gastrointestinal cancer, immuno-oncology, 3D in vitro models.

Cancer Genetics and Epigenetics research group

Group Leader

  • Sergio Alonso Utrilla, PhD
    Sergio Alonso Utrilla, PhD

    Sergio Alonso Utrilla, PhD

    Sergio Alonso has worked in the field of cancer genetics and epigenetics for nearly two decades. His work has resulted in over 40 scientific publications, showcasing his interdisciplinary expertise in molecular biology, cell biology, computational and statistical high-throughput data analysis. He obtained his PhD in Biochemistry and Molecular Biology at the Complutense University of Madrid in 2002, with internships at the Biotechnology Research Institute in Montreal (1998-99). Following a year of postdoctoral experience at the Center for Biological Research (CIB-CSIC, Madrid), Alonso joined Dr M. Perucho's team at The Burnham Institute for Cancer Research in La Jolla, CA (now Sanford Burnham Prebys Medical Discovery Institute, SBP) as a postdoctoral associate researcher in 2003.

    Alonso received the Fishman Fund Award for Exceptional Postdoctoral Researchers in 2006 and was subsequently promoted to Staff Scientist at SBP in 2007. In 2009, he transitioned with Dr Perucho's team to the newly established Institute of Predictive and Personalized Medicine of Cancer (IMPPC) to establish the Laboratory of Cancer Genetics and Epigenetics. IMPPC later merged into Germans Trias i Pujol Research Institute (IGTP) in 2016, where the research activities of CGE have been ongoing, with Alonso assuming leadership in 2019.

    Alonso has been an active member of European research networks EuCOLONGENE and TRANSCOLONCAN COST actions, representing CGE. He has also participated in the CRIPREV multicentric PERIS project to identify genetic, epigenetic, and metagenomic biomarkers of CRC risk in medium-risk populations. In 2023, Alonso's group joined the COST action IMMUNO-model (CA21135) to model immunotherapy response and toxicity in cancer.

    Contact: salonsou(ELIMINAR)@igtp.cat
    ORCID: 0000-0001-6497-892X

Research lines

Epigenetic biomarkers for cancer susceptibility and metastatic spread

The group are currently analyzing the impact of the alterations in patterns of DNA methylation in genome disruption and studying the applications of these epigenetic somatic alterations for gastrointestinal cancer diagnosis and prognosis. They generate very complete epigenomic profiles by using the most advanced methylation microarray platform, the Human EPIC arrays from Illumina. Specifically they are studying the epigenomics of proteolysis and the applications of epigenetic alterations in several members of the metalloproteinase gene family as biomarkers for defining individuals at high risk for field cancerization.  Also, these studies should yield tools predictive for metastatic homing tendency of primary colorectal cancers, and diagnostic for distinguishing primary ovarian cancers from metastatic gastrointestinal tumors.

DNA demethylation, predictive of the development of multiple colon cancers

Some colon cancer patients present synchronous cancers (multiple simultaneous cancers) at diagnosis and others develop later additional primary (metachronous) cancers, but the risk factors are unknown for nonhereditary colon cancer. The group has discovered that high levels of DNA demethylation in non-cancerous mucosa from patients who underwent primary colon cancer resection was predictive for metachronous neoplasms. They measure methylation using several bisulfite-treatement-based techniques, such as bisulfite sequencing and MS-QPCR. The levels of demethylation would serve as a prognostic biomarker that would allow for improved identification of individuals at high risk for the development of metachronous colorectal cancer. This would consequently lead to increased efficiency of surveillance and prognosis.

Targeting extracellular matrix remodelers to enhance lymphocytic infiltration and immunotherapy response in colorectal cancer

They have recently discovered that epigenetic silencing of some extracellular matrix remodelers associates with higher tumor immunogenicity. Thus, mimicking this silencing by genetic (shRNA, CRISPR and dCRISPR) or pharmacological (protease inhibitors or targeted antibodies) approaches might facilitate tumor immune recognition, and enhance the response to immune checkpoint therapies. They will test this hypothesis using in vitro models using 3D co-cultures of cancer cells, fibroblasts and lymphocytes. If successful, they will test the pharmacological approach in animal models.

Development of in vitro 3D co-culture models for cancer immunotherapy

They have initiated the development of flexible, affordable, and standardized in vitro models as an alternative to tumor organoids to study cancer immunotherapy response. These models will consist of 3D co-cultures of already established and commercially available colorectal cancer cell lines, together with human fibroblasts to form tumorspheres in a matrix of methylcellulose, which is significantly cheaper than the generally used matrigel-based matrices. After the formation of the tumorspheres, peripheral blood mononucleated cells (PBMCs) from healthy donors or cancer patients will be added to the co-cultures, to study their ability to infiltrate the tumorspheres. Lymphocytic infiltration will be quantified by immunodetection using flow cytometry.

Active projects

Extracellular matrix remodelers: association with lymphocytic infiltration and applicability as markers of response to immunotherapy in colon and rectal cancer

PI: Sergio Alonso
Funding agency: Fundación Mutua Madrileña
Duration: September 2020 - October 2024

Role of genomic hypomethylation in spontaneous tetraploidization and chromosomal instability: novel mechanistic insights in the early steps of colorectal oncogenesis

PI: Sergio Alonso Utrilla
Funding agency: Instituto de Salud Carlos III (ISCIII)
Agency code: PI21/01766
Duration: 01/01/2022 - 31/12/2024

Past projects

Remodeladores de la matriz extracelular: asociación con infiltración linfocítica y aplicabilidad como marcadores de respuesta a inmunoterapia en cáncer de colon y recto

PI: Sergio Alonso Utrilla
Funding agency: Fundación Mutua Madrileña
Agency code: AP174232020
Duration: 01/09/2020 - 31/08/2023

Genomic Hypomethylation: Association between aging and cancer through a singular oncogenic pathway

PI: Sergio Alonso Utrilla (as co-PI)
Funding agency: Instituto de Salud Carlos III (ISCIII)
Agency code: PI18/01484
Duration: 01/01/2019 - 31/12/2022

Scientific publications

Loi E, Zavattari C, Tommasi A, Moi L, Canale M, Po A, Sabato C, Vega-Benedetti AF, Ziranu P, Puzzoni M, Lai E, Faloppi L, Rullán M, Carrascosa J, Amat I, Urman JM, Arechederra M, Berasain C, Ferretti E, Casadei-Gardini A, Avila MA, Alonso S, Scartozzi M, Zavattari P. HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples. Br J Cancer. 2022 Jun;126(12):1783-1794. DOI: 10.1038/s41416-022-01738-1.

Poppova L, Pavlova S, Gonzalez B, Kotaskova J, Plevova K, Dumbovic G, Janovska P, Bystry V, Panovska A, Bezdekova L, Maslejova S, Brychtova Y, Doubek M, Krzyzankova M, Borsky M, Mayer J, Bryja V, Alonso S, Pospisilova S. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene. Epigenetics. 2022 Dec;17(12):1628-1635. DOI: 10.1080/15592294.2022.2050004.

González B, Fece de la Cruz F, Samuelsson JK, Alibés A, Alonso S. Epigenetic and transcriptional dysregulation of VWA2 associated with a MYC-driven oncogenic program in colorectal cancer. Sci Rep. 2018 Jul 23;8(1):11097. DOI: 10.1038/s41598-018-29378-7.

González B, Navarro-Jiménez M, Alonso-De Gennaro MJ, Jansen SM, Granada I, Perucho M, Alonso S. Somatic Hypomethylation of Pericentromeric SST1 Repeats and Tetraploidization in Human Colorectal Cancer Cells. Cancers (Basel). 2021 Oct 26;13(21):5353. DOI: 10.3390/cancers13215353.

Vymetalkova V, Vodicka P, Vodenkova S, Alonso S, Schneider-Stock R. DNA methylation and chromatin modifiers in colorectal cancer. Mol Aspects Med. 2019 Oct;69:73-92. DOI: 10.1016/j.mam.2019.04.002.

These are five highlighted publications by the group. A complete list of publications by the group members will soon be available on this page.

Additional information

Collaborative networks

IMMUNO-model: Modelling immunotherapy response and toxicity in cancer

The COST Action IMMUNO-model CA21135 aims to foster research and innovation in the field of preclinical immuno-oncology models with the ultimate goal of advancing in the treatment of cancer patients by improving their outcomes and quality of life.

The unprecedented change that immunotherapy has represented in the treatment of cancer is best illustrated by the spectacular results obtained in previously incurable malignancies, such as metastatic melanoma. However, the widespread use of these therapies has been hindered by their limited effectiveness and associated toxicities. A better understanding on the complex interactions between tumor cells and the immune system is strictly required to address these problems, and to develop more effective and safer immunotherapies. However, one of the most important obstacles in immuno-oncology research is the scarcity of preclinical models that faithfully recapitulate human immunity and contribute to identify novel therapeutic targets, characterize biomarkers of therapeutic response and toxicity, and generate reliable data on drug synergies.

IMMUNO-model will bring together European researchers from diverse sectors (academia, clinical, industry) with the common goal of establishing a Network that endorses immuno-oncology research by specifically promoting the sharing, standardization and application of immunotherapy preclinical models. This Action will allow the implementation of a broad, creative and collaborative hub through the organization of community-building activities, the creation of synergies among European and non-European scientists, and the training of future researchers in the field. The ultimate aim of this Action is to contribute to translate novel scientific discoveries into benefits to cancer patients and the society.

2022-2023 thesis

Title: DNA methylation alterations associated with genome endoreduplication and with tumor-infiltrating lymphocytes in colorectal cancer
Author: Maria Navarro Jiménez
Supervisors: Sergio Alonso Utrilla and Beatriz González Alonso
University: Universitat Autònoma de Barcelona
Date of defense: December 15th 2023

Master’s theses

Title: Characterization of three-dimensional co-cultures of colorectal cancer cell lines
Author: Gisela de Miguel Garcia
Supervisors: Sergio Alonso Utrilla and Beatriz González Alonso
University: Universitat Autònoma de Barcelona
Date of defense: 6 September 2023

Title: Molecular characterization of gastric cancers: genetic mutations, global DNA methylation and presence of cancer-related pathogens
Author: Marta Pérez López
Supervisors: Sergio Alonso Utrilla and Beatriz González Alonso
University: Universitat Pompeu Fabra (UPF)
Date of defense: 25 June 2023

Title: Epigenetic alterations in the JAK3/STAT3 pathway in colorectal cancer
Author: Catarina Sofia Ferrera Violante
Supervisors: Sergio Alonso Utrilla and Federico Herrera
University: Universidade de Lisboa
Date of defense: July 2024

Title: Epigenetic alterations in AOX1, TBX20 and BMP3 associated with increased tumour immunogenicity in colorectal cancer
Author: Anna Pujol Cano​​​​​​​
Supervisors: Sergio Alonso Utrilla and Beatriz González Alonso​​​​​​​
University: Universitat Autònoma de Barcelona
Date of defense: July 2024

News

- Campus Can Ruti

The IGTP presents CARE Translational Program in Cancer Research

CARE, the Translational Program in Cancer Research is the first transversal program promoted by the Germans Trias i Pujol Research Institute (IGTP), and it aims to become a bridge for researchers in the field of cancer who want to bring basic and clinical research together, so that the knowledge and the tools generated in the laboratory can benefit the patient.

- Research

Funding for a project focussed on the response to immunotherapy for the treatment of colorectal cancer

This year the Fundación Mutua Madrileña has allocated 2.3 million euros for financing medical research in Spain. Four of the 21 clinical studies benefiting are projects being carried out in Catalan research centres, which will receive a total of 540,000 euros. One of these is being led by the Germans Trias I Pujol Research Institute (IGTP) and coordinated between four groups of the Programme for Predictive and Personalized Medicine of Cancer (IGTP-PMPPC).

+ News

Contact

Sergio Alonso Utrilla

(+34) 93 554 3050 extn: 3063

salonsou(ELIMINAR)@igtp.cat