CRIG 'young investigator proof-of-concept projects’: laureates 16th call
In collaboration with vzw Kinderkankerfonds, CRIG provides research grants for young (postdoctoral and/or senior doctoral) cancer researchers at CRIG to initiate potentially high-risk and innovative cancer research projects. In this 16th call, following postdocs were awarded, and have started their project in this month.
Dr. Jesse Demuytere – 'Mapping the microenvironment of colorectal peritoneal metastases using spatial transcriptomics’ (promotors of the grant: Prof. Geert Berx & Prof. Wim Ceelen) - The incidence of colorectal cancer is increasing. In one in ten cases, colorectal cancer metastasizes to the peritoneum, the membrane lining the abdominal cavity. Despite the grim prognosis of patients with peritoneal metastases, these metastases remain understudied. In this project, we aim to study the composition and architecture of the tumor microenvironment (TME), with a particular focus on cancer-associated fibroblasts and their origin. To do so, we will utilize the MERSCOPE spatial transcriptomics platform which allows for visualization of hundreds of genes in subcellular resolution. We previously created a single-cell transcriptomic atlas of colorectal peritoneal metastases and we will integrate the spatial information we acquire into this atlas. This will result in a spatially resolved single-cell atlas of these metastases, building a platform for further research, particularly studying how tissue niches create an immunosuppressive and therapy-resistant tumor microenvironment.
Dr. Lisa Depestel – ‘Synergistic drug interactions with CPSF3 controlled DNA damage response signaling as potential therapy for high-risk neuroblastoma’ (promotor of the grant: Prof. Nadine Van Roy, PI of the lab: Prof. Kaat Durinck) - Neuroblastoma (NB) is the most frequent extra-cranial pediatric tumor. Genomic profiling has demonstrated that NBs are mutationally silent with a typical pattern of highly recurrent segmental chromosomal imbalances. In search for novel druggable targets, we performed an integrative genomics analysis of DNA copy number and gene expression data of a large series of primary NB cases allowing us to identify ‘Cleavage and Polyadenylation Specific Factor 3’ (CPSF3) as a potential new therapeutic target. Notably, CPSF3 was recently shown to be a key druggable target in amongst others ovarian cancer, pancreatic cancer, acute myeloid leukemia and Ewing sarcoma. In this project, Lisa will further investigate whether CPSF3 is indeed a promising druggable target in high-risk neuroblastoma.
Dr. Laura Guerrero – ‘The impact of disrupted one-carbon metabolism on RNA homeostasis in T-cell acute lymphoblastic leukemia’ (promotor of the grant: Prof. Panagiotis Ntziachristos) - T-cell acute lymphoblastic leukemia (T-ALL) is a severe hematological malignancy stemming from the malignant transformation of T-cell progenitors, affecting both children and adults. Although the prognosis has improved with the advent of intensified chemotherapy, the outcomes for patients with primary resistant or relapsed leukemia remain poor. This underscores the critical need for innovative therapeutic approaches that are more effective and less toxic. Recent advancements in the understanding of cancer biology have highlighted the crucial roles of cellular metabolism and transcriptional regulation in the pathogenesis of T-ALL and other malignancies. In Prof. Ntziachirstos' group, we focus on studying epigenetics, alternative splicing and RNA methylation, and other mechanisms controlling transcriptional output, with the aim of developing new alternative therapies for high-risk T-ALL patients. For that purpose, we develop preclinical models, including PDX models to test new therapeutic approaches that can potentially lead to a better outcome for resistant or relapsed patients that do not respond to current treatments. Particularly, in this proof of concept project, Laura will use preclinical T-ALL models to focus on the unexplored connection of metabolism and transcriptional regulation in T-ALL as a targetable vulnerability of cancer cells.
Drs. Maude Jans – ‘Targeting genotoxic pks+ E.coli to prevent colorectal cancer development using an innovative translational technology’ (promotor of the grant: Prof. Geert van Loo) – Specific members of the gut microbiota, known as 'oncobacteria,' can drive colorectal cancer initiation and progression. One such oncobacterium is pks+ Escherichia coli, which produces the genotoxin colibactin, capable of inducing DNA damage and promoting colorectal cancer (CRC) progression. Remarkably, the abundance of pks+ E. coli increases in conditions of inflammation and cancer. We recently unraveled the molecular mechanism by which pks+ E. coli bind intestinal epithelial cells, which enables colibactin-mediated genotoxicity. We identified two crucial bacterial adhesins, FimH and FmlH, as crucial components in this binding mechanism. Targeting these adhesins using small molecule inhibitors can prevent binding, but requires continuous treatment and does not eliminate the pathogen from the gut. In collaboration with Prof. Han Remaut’s lab (VUB), this project aims to develop and validate a novel therapeutic strategy using nanobody-coated protein fibers (Bactocatch) targeting pks+ E. coli. These coated fibers are designed to selectively agglutinate and remove pks+ E. coli from the gut, preventing bacterial adhesion and colibactin-induced genotoxicity. This preclinical study could lay the groundwork for targeted therapies that reduce CRC risk while preserving the integrity of the gut microbiota.
Dr. Sam Kint – 'Dissecting epigenetic plasticity at spatial resolution in breast tumors by measuring DNA methylation’ (promoter of the grant: Prof. Jo Vandesompele, PI of the lab Prof. Katleen De Preter) - Recent advances in the development of several single-cell and spatial -omics methods enabled in depth profiling of most biologic layers within cells or tissues at varying resolution. Spatial epigenomic methods that can be used to measure histone marks or nucleosome occupancy are described. However, to date, no genome-wide spatial DNA methylation profiling method has been described. In this project, we will use a recently acquired photolithographic DNA printer to develop a spatial DNA methylation analysis method. This method will be used to spatially study the epigenome in triple negative breast cancer samples, and acquire fundamental insights in how non-genetic drivers steer epithelial to mesenchymal plasticity (EMP) and how this process is influenced by the tumor microenvironment.
Drs. Alexandra Thiran – 'Study of the CRC-promoting function of Candida albicans in early and advanced mouse models of CRC’ (promoter of the grant: Prof. Lars Vereecke) - Colorectal cancer (CRC) is increasingly common, especially in younger people, with growing evidence that the intestinal microbiota, including bacteria and fungi like Candida albicans, play a significant role in its development. This project aims to investigate C. albicans' role in CRC using two mouse models, focusing on early-stage CRC (goblet- and Paneth cell depleted mice – Muc2DTA/+) and advanced CRC (KPN and AKPT intracolonic organoid injections). We will analyze the effects of C. albicans on tumor development and immune response through IHC, flow cytometry and bulk-RNA sequencing. In parallel, the presence of C. albicans in clinical CRC samples will also be examined. The findings of this project could reveal new insights into how C. albicans promotes CRC progression.
Dr. Jelle Vandersteene – 'Attract to kill: Motility trapping as a novel therapeutic strategy for
high grade glioma’ (promoter of the grant: Prof. Robrecht Raedt) - The treatment strategy for high-grade glioma (HGG) typically combines systemic and local therapy. Local therapy is hindered by anatomical constraints (eloquent brain) and by tumor motility. HGG cells are highly mobile, infiltrating nearby and more distant brain regions where they hide within healthy brain tissue and evade local therapy. To target these cells, we are dependent on systemic therapy, which is limited by the blood-brain barrier. Preventing tumor progression thus remains a major challenge, highlighting the need for innovative therapeutic strategies for HGG. In this project, Jelle will investigate the disruption of the migratory pattern of HGG through motility trapping. This principle entails synthetically administering their migratory cues at the primary tumor site to attract the migratory tumor cells, where they become susceptible to subsequent local therapy.
