Research
Hereditary colorectal cancer syndromes. My research group is dedicated to study genetic syndromes predisposing to colorectal cancer. This population is relevant to develop our understanding of intestinal carcinogenesis, define the landscape of somatic mutations in premalignant lesions, develop novel cancer interception strategies and discover novel genes that predispose to the development of colorectal cancer. We have published in the Journal of Clinical Oncology that at least 35% of patients diagnosed with colorectal cancer under age 35 had a clinical diagnosis of a Hereditary Cancer Syndrome. In addition, we have clinically described in detail for the first time the genotype, somatic tumor studies and outcomes of Lynch Syndrome patients diagnosed with rectal cancers.
Genomic landscape of premalignancy. Cancer Interception (formerly known as chemoprevention) drug development depends on obtaining a detailed description on the somatic mutation landscape transcriptomics and immune profiling of premalignant lesions. We have recently published our initial results on the mutatome and allelic imbalances of colorectal adenomas from FAP patients. We also described the immuneprofile and neoantigen repertoire of premalignant lesions in patients with Lynch syndrome which is independent of the mutational rate, thus setting a new model of progression in mismatch repair deficient premalignancy. Based on these findings, we have taken a systems biology approach and used gene expression tools associated with bioinformatics analysis to uncover drugs to target premalignant lesions by creating a framework called ‘Cancer In Silico Drug Discovery’ (CIDD) and also to classify colorectal precancer lesions in deficient molecular subgroup using the consensus molecular classification (CMS).
Development of organoids as an in vitro platform for carcinogenesis and drug development studies. My group has been actively involved in the development of a colorectal organoid platform derived directly from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (PSCs). Our contribution has been essential to validating the translational application of this model to the human context by comparing the hESC- and PSC-derived organoids to our patient-derived organoids and their transcriptomic data (mRNA-seq). In addition, we have investigated the contribution of transcription factors SPDEF and ATOH1 to colorectal carcinogenesis and their potential application to arrest premalignancy development using our unique ex vivo organoid platform.
Molecular biology of mismatch repair deficiency and its association to clinicopathological profiles, prognosis and sensitivity to chemotherapeutic agents. Colorectal cancers displaying high levels of Microsatellite Instability (MSI-H) have distinct molecular, prognostic and predictive features. My doctoral work was based on studying in vitro the sensitivity of MSI-H colorectal cancer cell lines to Irinotecan and confirmed that MSI-H cell lines are responsive to Irinotecan. I continued this line of research during my post-doctoral fellowship and led work to identify novel drugs for this cancer subtype with two manuscripts that described two novel targeted strategies for MSI-H tumors. The first manuscript utilized a systems biology tool called the Connectivity Map that uncovered that compounds targeting the PIK3-AKT-mTOR pathway are specific for MSI tumors. The second paper identified a gene defect that is present in 85% of MSI tumors, which is a mutation in the gene MRE11. This gene is involved in the double strand break repair and its mutation among MSI tumors is secondary to the hypermutability induced by MMR deficiency. I have described in this seminal contribution the synthetic lethality combination between defects in MRE11 and PARP inhibition. Finally, I have provided with a comprehensive review of the field of mismatch repair deficient colorectal cancers which has been an important reference in the field.