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