ERC FUNDED PROJECTS

Cancer genome sequencing has led to a paradigm shift in our understanding of oncogenesis. It has identified thousands of genetic alterations that segregate into two groups, a small number of frequently mutated genes and a much larger number of infrequently mutated genes. The causative role of frequently mutated genes is often clear and are the focus of concerted therapeutic development efforts. The role of those infrequently mutated is often unclear and can be difficult to separate from ‘mutational noise’. Determining the relevance of low frequency mutations is important for providing a full understanding of processes driving tumourigenesis and if functionally relevant may have broader implications on the applicability of targeted therapies. This project aims to begin addressing this by defining the function of all genes mutated in colorectal cancer (CRC) in the earliest stages of tumour formation. I have performed a whole genome screen in a 3D organoid CRC initiation model identifying several potentially important mediators of this process. Crucially, some of these genes are mutated in CRC at low frequency but not described as cancer driver genes. Thus, I hypothesize that rather than ‘mutational noise’ infrequently mutated genes contribute to CRC initiation. I will test this by addressing two aims: 1) Determine the role of genes mutated in CRC during tumour initiation 2) Validate and determine the function of a subset of identified genes potentially defining novel cancer mechanisms I will use a combination of CRISPR genetic disruption in state-of-the-art 3D mouse and human organoid cultures and advanced mouse models to address these aims. This comprehensive approach will provide a foundation for understanding the importance of the entire spectrum of mutations in CRC and open new avenues of research into the function of these genes. More broadly, it has the potential to make a profound impact on how we think about tumourigenic mechanisms and cancer therapeutics.

1 498 618 €

Start date: 2017-08-01, End date: 2022-07-31

Over many years, our research group has explored the complex relationship between cancer and ageing. As part of this work, we have generated mouse models of protease deficiency which are protected from cancer but exhibit accelerated ageing. Further studies with these mice have allowed us to unveil novel mechanisms of both normal and pathological ageing, to discover two new human progeroid syndromes, and to develop therapies for the Hutchinson-Gilford progeria syndrome, now in clinical trials. We have also integrated data from many laboratories to first define The hallmarks of ageing and the current possibilities for Metabolic control of longevity. Now, we propose to leverage our extensive experience in this field to further explore the relative relevance of cell-intrinsic and -extrinsic mechanisms of ageing. Our central hypothesis is that ageing derives from the combination of both systemic and cell-autonomous deficiencies which lead to the characteristic loss of fitness associated with this process. Accordingly, it is necessary to integrate multiple approaches to understand the mechanisms underlying ageing. This integrative and multidisciplinary project is organized around three major aims: 1) to characterize critical cell-intrinsic alterations which drive ageing; 2) to investigate ageing as a systemic process; and 3) to design intervention strategies aimed at expanding longevity. To fully address these objectives, we will use both hypothesis-driven and unbiased approaches, including next-generation sequencing, genome editing, and cell reprogramming. We will also perform in vivo experiments with mouse models of premature ageing, genomic and metagenomic studies with short- and long-lived organisms, and functional analyses with human samples from both progeria patients and centenarians. The information derived from this project will provide new insights into the molecular mechanisms of ageing and may lead to discover new opportunities to extend human healthspan.

2 456 250 €

Start date: 2017-09-01, End date: 2022-08-31

Obesity and related co-morbidities give rise to severe health and socioeconomic problems. Surgical treatment for obesity (bariatric surgery) is remarkably effective in the control of morbid obesity and rapid resolution of Type 2 Diabetes, and the number of such procedures is increasing rapidly in many obesity-prevalent countries. We, and others, have demonstrated that surgical interventions such as Roux-en-Y Gastric Bypass (RYGB) modulates gut hormone levels, induces systemic metabolic changes and results in the shift of the microbiome from Firmicutes to the Proteobacteria phylum. Although the gut microbiota have been implicated in the reduction of adiposity post-surgery, the long-term effect of altered gut microbiota on patients who have undergone RYGB, remains to be studied. Our recent data suggested that microbial activities are highly associated with inflammation and cancer. My research programme aims to investigate the RYGB-specific gut microbiota impacts on host physiology and colon cancer risk. To achieve this goal, I will employ a multidisciplinary approach that combines systems biology techniques with a bottom-up approach. This work will deliver phenotypic and mechanistic characterisation of the interplay between the host and the gut microbiota. The research findings will significantly contribute towards the understanding of fundamental molecular and cellular processes that are key in host and gut microbiota interactions. This will provide knowledge-based evidence of the gut microbial impact on human physiology, and has the potential to unravel novel prevention targets and promote a more thorough healthcare strategy for bariatric patients.

1 499 091 €

Start date: 2017-08-01, End date: 2022-07-31

The Glioblastoma Multiforme (GBM) is the most common primary brain tumor and it is incurable. Two major challenges affect GBM clinical management: its heterogeneity (which treatment will best fit this very patient?) and its resistance to available treatments (will the patient benefit in any way from the chosen therapy?). Here we approach these questions with a personalized entry point. First, we aim to create “humanized” experimental models of GBM accurately reflecting patients at molecular level. These GBM Subtype Avatars models (GSA) will be exploited as “targeted patients” in personalized biology and intervention studies. Since GBM exists as molecular subtypes with similar histopathology but mutually exclusive genetic lesions and molecular features, we will generate GSA by targeting mutations recurrently associated with Proneural, Classical or Mesenchymal GBM subtypes into adult human neural stem cells (NSC). Evidence supports that these cells can give rise to high-grade gliomas when engineered with the appropriate genetic lesions. Next, engineered NSC will be orthotopically implanted into immunocompromised rats and the resulting tumors profiled for gene expression, DNA methylation and copy number aberrations. These profiles will be compared to those generated in patient-derived xenografts and biopsies. Second, to identify drug targets favoring patients’ response to the current standard of care, we will exploit GSA for state-of-art genetic screens in vivo. Specifically, we will seek for synthetic lethal interactions between DNA damaging agents and the GSA transcriptome using an in vivo CRISPRi screening approach. Third, to investigate the molecular basis of GBM heterogeneity in GSA models, we will combine genetic and immunophenotypic tracing with gene expression and epigenomic profiling. Identifying tumor-specific vulnerabilities in a dismal disease urging for effective therapies and its molecular fingerprinting convey conceivably rapid Translation in Oncology.

1 500 000 €

Start date: 2017-07-01, End date: 2022-06-30