This research group investigates genetic and epigenetic alterations that impact the development of colorectal cancer (CRC) and gastric cancer, as well as their corresponding tumor phenotypes. Its research has led to the identification of epigenetic silencing of genes encoding extracellular metalloproteinases, which has significant implications for cancer metastatic potential and cancer risk [1,2].
This discovery sparked their interest in investigating the epigenetic alterations in all extracellular matrix (ECM) metalloproteinases, leading to the discovery of frequent and coordinated hypermethylation of ADAMTS genes . Additionally, their researchers have identified methylation alterations in other genes that have a substantial impact on CRC phenotype [4,5]. They have also developed microarray-based technologies to analyse genomic methylation  and discovered highly specific and sensitive epigenetic biomarkers for biliary cancer detection .
Their studies have extensively investigated DNA hypomethylation of genes and repetitive elements in gastrointestinal cancers, identifying that aberrant genomic demethylation of the mucosa is a risk factor for gastric and colorectal cancer development [8,9,10,11,12]. They have found that hypomethylation of a particular repetitive DNA element is associated with aberrant genome duplication, which is believed to be an early step in the development of CRC as it increases the probability of aneuploidy .
Their current research aims to explore the molecular mechanisms underlying this association between hypomethylation of several repetitive DNA elements and aberrant genomic duplication, which could reveal fundamental factors in the early stages of tumorigenesis preceding malignant transformation.
Recently, this group has initiated a new research line to explore epigenetic alterations associated with CRC immunogenicity, which has 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 tumor immunogenicity, resulting in more abundant lymphocytic infiltration and enhanced response to immune checkpoint inhibitor therapy.
Keywords: Gastrointestinal cancer, epigenomics, genomics, immuno.
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.
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
Start date: 01/01/2019
End date: 31/12/2022
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
Start date: 01/09/2020
End date: 31/08/2023
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
Start date: 01/01/2022
End date: 31/12/2024
Alonso S, González B, Ruiz-Larroya T, Durán Domínguez M, Kato T, Matsunaga A, Suzuki K, Strongin AY, Gimènez-Bonafé P, Perucho M. Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer. Clin Epigenetics. 2015 Dec 2;7:124. DOI: 10.1186/s13148-015-0158-1.
Alonso S, Dai Y, Yamashita K, Horiuchi S, Dai T, Matsunaga A, Sánchez-Muñoz R, Bilbao-Sieyro C, Díaz-Chico JC, Chernov AV, Strongin AY, Perucho M. Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget. 2015 Feb 20;6(5):3420-31. DOI: 10.18632/oncotarget.2852.
Alonso S, González B, Alibés A, Perucho M. Analysis of Somatic DNA Methylation Alterations of Genes Encoding Cell Surface Metallopeptidases in Colorectal Cancer. Methods Mol Biol. 2018;1731:271-294. DOI: 10.1007/978-1-4939-7595-2_24.
Muto Y, Maeda T, Suzuki K, Kato T, Watanabe F, Kamiyama H, Saito M, Koizumi K, Miyaki Y, Konishi F, Alonso S, Perucho M, Rikiyama T. DNA methylation alterations of AXIN2 in serrated adenomas and colon carcinomas with microsatellite instability. BMC Cancer. 2014 Jun 25;14:466. DOI: 10.1186/1471-2407-14-466.
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.
Koizumi K, Alonso S, Miyaki Y, Okada S, Ogura H, Shiiya N, Konishi F, Taya T, Perucho M, Suzuki K. Array-based identification of common DNA methylation alterations in ulcerative colitis. Int J Oncol. 2012 Apr;40(4):983-94. DOI: 10.3892/ijo.2011.1283.
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.
Samuelsson J, Alonso S, Ruiz-Larroya T, Cheung TH, Wong YF, Perucho M. Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer. Int J Oncol. 2011 Jun;38(6):1575-7. DOI: 10.3892/ijo.2011.972.
Kamiyama H, Suzuki K, Maeda T, Koizumi K, Miyaki Y, Okada S, Kawamura YJ, Samuelsson JK, Alonso S, Konishi F, Perucho M. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene. 2012 Nov 29;31(48):5029-37. DOI: 10.1038/onc.2011.652.
Leodolter A, Alonso S, González B, Ebert MP, Vieth M, Röcken C, Wex T, Peitz U, Malfertheiner P, Perucho M. Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer. Clin Transl Gastroenterol. 2015 Apr 30;6(4):e85. DOI: 10.1038/ctg.2015.14.
Samuelsson JK, Dumbovic G, Polo C, Moreta C, Alibés A, Ruiz-Larroya T, Giménez-Bonafé P, Alonso S, Forcales SV, Manuel P. Helicase Lymphoid-Specific Enzyme Contributes to the Maintenance of Methylation of SST1 Pericentromeric Repeats That Are Frequently Demethylated in Colon Cancer and Associate with Genomic Damage. Epigenomes. 2017 Jun;1(1):2. DOI: 10.3390/epigenomes1010002.
Dumbovic G, Biayna J, Banús J, Samuelsson J, Roth A, Diederichs S, Alonso S, Buschbeck M, Perucho M, Forcales SV. A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer. Nucleic Acids Res. 2018 Jun 20;46(11):5504-5524. DOI: 10.1093/nar/gky263.
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.
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.
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).