CRIG 'young investigator proof-of-concept projects’: laureates 17th 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 17th call, following postdocs were awarded, and have started their project in this month.
Dr. Jeffrey Aalders – 'Optimizing CAR-T cell development by navigating human pluripotent stem cells in a cell-cycle specific roadmap’ (promotor of the grant: Prof. Tom Taghon) - CAR T-cell therapy is an immunotherapy where the T-cells are modified to better recognize and kill cancer cells. Despite the advancements in CAR T-cell therapy, the approach still suffers from lack of broad availability and cost-efficiency. The current approach modifies the patients’ own T-cells (autologous) ex vivo, but these have subpar quality and the production time also hampers prompt treatment and is costly. The Taghon lab aims to develop more efficient cell therapies using human pluripotent stem cells (iPSCs) to generate both hematopoietic stem cells (HSCs) and CAR T-cells. However, current methods lack efficiency for large-scale, GMP-compliant production. We expect that culture heterogeneity negatively affects the differentiation efficiency. As this heterogeneity could be explained, at least in part, by variations in cell-cycle states, in this project, Jeffrey will investigate how the cell-cycle status of iPSCs impacts in vitro human T-cell generation.
Dr. Robin Demuynck – 'Investigating the mechanism of sensing and cytotoxic responses by endothelial cells during ICD-based therapies’ (promotor of the grant: Prof. Dmitri Krysko) - Immunogenic cell death (ICD) enhances anti-cancer immune responses by increasing tumor adjuvanticity and antigenicity. While endothelial cells (ECs) are typically associated with an immunosuppressive tumor microenvironment (TME), the team of Robin Demuynck and Faye Naessens in the CDIT laboratory, led by Prof. Krysko, has shown that ECs can engulf cancer cells undergoing ICD, leading to their activation and increased antigen presentation. Vaccination with ICD-exposed ECs boosts antigen-specific T-cell responses and extends tumor-free survival in mice, highlighting ECs as non-professional antigen-presenting cells with potential immunotherapeutic relevance. In this project, Robin aims to elucidate the mechanisms underlying EC immunosurveillance and their role in shaping anti-tumor immunity. Using CRISPR-engineered ECs, in vivo vaccination models, and scRNA sequencing, key regulatory pathways governing EC-mediated immune responses will be analyzed, ultimately paving the way for novel ICD-based immunotherapies targeting ECs within the TME.
Dr. Mamadou Amadou Diallo – 'Targeted activation of ZBP1 for cancer therapy using a nucleotide-based approach’ (promotor of the grant: Prof. Peter Vandenabeele, PI of the group: Prof. Jonathan Maelfait) - In his project, Mamadou aims to develop a DNA-based strategy to selectively activate ZBP1-mediated cell death in tumors. By designing and optimizing Z-DNA analogs that trigger ZBP1 activation, he aims to mimic the conditions of Z-nucleic acid sensing, similar to those observed during viral infections. This approach exploits the innate immune response to induce cell death, offering a potential therapeutic strategy. To achieve this, he will rationally design Z-DNA analogs that selectively engage ZBP1 in tumors while minimizing off-target effects. These engineered probes will be first validated through in vitro assays. Once optimal candidates are identified, tumor-specific delivery strategies such as nanocarriers or aptamer conjugation will be explored and the most promising candidates will be tested in preclinical mouse models to assess their therapeutic potential.
Dr. Nele Loret – 'Assessing the anti-metastatic effect of L-asparaginase in PDX models of triple-negative breast cancer’ (promotor of the grant: Prof. Steven Goossens) - Triple-negative breast cancer (TNBC) is associated with an aggressive and invasive phenotype and poor clinical outcomes, highlighting the need for alternative, improved therapeutic strategies. Recent data have shown that invasive TNBC cells lose expression of asparagine synthetase (ASNS), making them dependent on exogenous uptake of asparagine. As such, they become sensitive to asparagine deprivation therapy. To target this vulnerability, the group of Prof. Goossens developed a more tolerable humanized, glutaminase-free asparaginase (EBD-200) and demonstrated its efficacy in significantly reducing metastases in a MMTV-PyMT breast cancer mouse model. In her project, Nele will investigate whether EBD-200 can prevent metastases in more clinically relevant patient-derived breast cancer models, in both adjuvant as well as neoadjuvant setting.
Dr. Annelien Morlion – 'Enriching cancer signals in blood plasma cell-free RNA through custom mRNA capture sequencing’ (promotors of the grant: Prof. Pieter Mestdagh & Prof. Jo Vandesompele) - The minimally invasive nature of liquid biopsies, such as blood (plasma) samples, makes them a valuable resource for detecting cancer biomarkers. RNA is produced in every cell according to its specific needs, and as cells throughout the body release genetic material into the bloodstream, circulating RNA signals can provide insight into cellular activity, including that of cancer cells and their surroundings. However, most cell-free RNA in blood plasma originates from blood cells, potentially masking weaker cancer-related signals from solid tumors. To increase sensitivity in detecting cancer signals, Annelien aims to develop a cost-effective, targeted RNA capture sequencing method. This involves designing probes that selectively target cancer- and tissue-specific RNAs and generating these custom probes using a photolithographic DNA printer. By overcoming the dominance of blood cell-derived RNAs, this targeted capture approach can improve the detection of target RNAs in blood plasma without the need for ultra-deep sequencing. Using this method, Annelien wants to uncover cancer-derived RNA signals in the blood plasma of liver, ovarian, and pancreatic cancer patients. In the future, the approach can be expanded to other cancers and sample types.
Dr. Tijl Vermassen – 'Decoding the N-glycome of extracellular vesicles (EVs) in expressed prostatic secretion (EPS)-urine’ (promotors of the grant: Prof. Sylvie Rottey & Prof. An Hendrix) - Prostate cancer is the second most common malignancy in men worldwide. Moreover, despite the excellent prostate cancer care in Belgium, 10-20% of patients will eventually experience disease progression following primary therapy. Therefore, it is imperative to understand which processes lead to disease progression in prostate cancer. The group of Prof. Rottey previously demonstrated that the total N-glycan profile of EPS urine (urine obtained after rectal examination of the prostate) shows diagnostic potential (discrimination between healthy, benign and malignant conditions) and prognostic potential (information on the disease course following primary therapy). It was also illustrated that EVs are abundantly present in the EPS urine of patients with prostate cancer. The group of Prof. Hendrix on the other hand has evaluated the proteome of EPS urine-derived EVs. As it is clear from literature that cancer-related EVs play a fundamental role in the development of metastatic disease and that N-glycans can regulate protein migration, recognition and interaction, Tijl will now investigate the N-glycome of EPS urine-derived EVs, to gain fundamental insights in the glycobiology of prostate cancer EVs and how this process contributes to the eventual metastatic disease in prostate cancer.
