Title Abstract "Long noncoding RNAs in cancer: deciphering the functional role of the dark matter of the human cancer genome" "The human genome is pervasively transcribed and produces thousands of yet unexplored long non-coding RNAs (lncRNAs). With this project, we aim to uncover novel lncRNAs with therapeutic or biomarker potential in cancer. This is achieved through an elaborate discovery and validation workflow, supported by novel laboratory technologies and data analysis strategies that will be implemented during the course of this project." "Long noncoding RNAs in cancer: deciphering the functional role of the dark matter of the human cancer genome" "The human genome is pervasively transcribed and produces thousands of yet unexplored long non-coding RNAs (lncRNAs). With this project, we aim to uncover novel lncRNAs with therapeutic or biomarker potential in cancer. This is achieved through an elaborate discovery and validation workflow, supported by novel laboratory technologies and data analysis strategies that will be implemented during the course of this project. 1.8 Disciplinecodes" "Feasibility and safety of a WT1-targeted cancer vaccine in patients with malignant mesothelioma and locally advanced breast cancer: an open label phase I trial." "Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Laboratory Experimental Medicine and Pediatrics (LEMP), Vaccine & Infectious Disease Institute (VAXINFECTIO)" "The Wilms' tumor 1 (WTI) protein has been shown to be a universal tumor antigen overexpressed in many tumors, including malignant mesothelioma and breast carcinoma. In view of the T cell immunogenicity of WTI-derived peptides, immunostimulatory dendritic cells loaded with WT1 antigen hold promise as a universal, yet patient-specific, polyepitope cancer vaccine to treat residual disease. Here, autologous monocyte-derived dendritic cells will be transfected with mRNA coding for the entire WT1 antigen and injected intradermally as a cellular cancer vaccine in mesothelioma and breast cancer patients as adjuvant treatmentafter optimal debulking or after neo-adjuvant chemotherapy. In this project, we want to investigate the safety, feasibility and immunogenicity of such WTI-targeted cancer vaccine in an open-label phase I trial." "Coping with breast cancer: research into the value and impact of the provision of psychosocial support for breast cancer patients" "The funding VLK bottom-up initiatives for the psychosocial support of cancer patients creates a situation that offers very good opportunities to examine which forms of psychosocial care cancer patients value most. The bottom-up strategy, after all, has a variety of initiatives for a result that allows patients to be operated which are similar to a large extent. What psychosocial care cancer patients value most is not known. There are a number of avenues that are important, and that this proposed research may shed further light. Certainly not all cancer patients will receive prefer formal psychological help. Earlier research has shown that some people want to avoid the help of a psychologist (or social worker). The reason is probably that they help put their aid indigence in the paint while they just seek to ""normal life"" again to pick up and take control of it is extremely important to himself again. Himself rise from the chaos in which they have fallen by the disease, is obviously very important, and that it ""therapy"" is part of a psychologist not. How big the group course of their treatment, and their psychological and social problems in passing be discussed. They may try to get out the car itself; if it fails, there is the breast nurse, who can if they have to arrange contact with the psychologist. Incidentally, it appears in the study of Ronse (albeit with a limited sample) that when the patient is in the hospital, the threshold to the psycholooh is smaller. From the (also limited) qualitative research participants to Eureka similar picture: the participants are very valuable psychosocial support (by psychologists Data transfer), but would have been reluctant to participate if there was gravity. The exercise also shows that psychosocial support more the character of ""encore""." "Coevolution of epithelium in colorectal cancer: comprehensive characterization of progress-associated tumor heterogeneity in the colorectal cancer" "Sabine Tejpar" "Digestive Oncology" "To understand the characteristics of colorectal cancer (CRC), diverse molecular classifiers have been generated. But these only capture the characteristics of the tumor at a specific stage or in a specific section. CRC has continuously evolving entities, with a complex adenoma-carcinoma sequence and later carcinoma-metastasis sequence, in a continuous coevolutionary crosstalk with the tumor microenvironment. Our past work has shown representative features in the carcinoma, and the current work will elaborate these in detail, integrating different data inputs needed to characterize the dynamic information in these lesions. The adenoma-carcinoma stages of CRC offer a unique opportunity, if exploited well, to understand evolutionary trajectories of the epithelium, the co-evolution of the TME and the possible impact on the targetable immune states. With this project, I will characterize the tumor cells’ sub-characteristics within classified epithelial molecular groups with integration approaches of bulk, single-cell and spatial technologies. In the preliminary data, the heterogeneous pattern within molecular subtypes can clearly be found. Especially, the understudied non adenomatous lesions, non-canonical Wnt driven tumors show very interesting heterogeneity and novel cancer stem cell dynamics. Collectively, signatures combined with bulk-, single-cell RNA sequencing and spatial techniques will identify the optimal stratification for CRC prognosis and therapy." "Long noncoding RNAs in cancer: deciphering the functional role of the dark matter of the human cancer genome" "Jo Vandesompele" "Department of Human Structure and Repair, Department of Biomolecular Medicine, Department of Radiation oncology and experimental cancer research, Department of Biochemistry, Department of Pediatrics and medical genetics" "The human genome is pervasively transcribed and produces thousands of yet unexplored long non-coding RNAs (lncRNAs). With this project, we aim to uncover novel lncRNAs with therapeutic or biomarker potential in cancer. This is achieved through an elaborate discovery and validation workflow, supported by novel laboratory technologies and data analysis strategies that will be implemented during the course of this project." "STAND UP TO CANCER: Integration of individual cancer genes in signalisation network in pediatric tumors" "Department of Biomedical molecular biology" "geen abstract" "Cell-cell cOmmuNicaTion As a driver of Cancer cell state identiTy - Decoding the impact of cell-cell communications on the identity of tumor states in skin cancers" "Yvan Saeys" "Department of Applied Mathematics, Computer Science and Statistics, KU Leuven, Université Libre de Bruxelles, Imec" "Different tumor states (TS) exist within a given tumor with some cancer cells actively dividing, while others differentiate, invade the surrounding tissues, give rise to metastasis, or are in a dormant and therapy-resilient state. The identification of the intrinsic and extrinsic mechanisms that modulate TS diversity is essential for the development of new therapeutic strategies. In this project, we will dissect the mechanisms by which stromal-cancer cell communications influence the gene regulatory networks (GRNs), that defined TS identity in skin cancers. We will take advantage of recent advances in single-cell lineage tracing, single-cell (spatial) multi-omics, microfluidics and bio-informatics to map the spatial distribution of the different TS and their neighboring stromal cells, study how these cellular and molecular (e.g. ligand/receptor) interactions remodel the GRNs and epigenome of cancer cells and thereby regulate their specific TS identity. We will use dynamic models to assess how these interactions evolve during tumor progression, metastasis, and in response to therapy. We will reconstitute or deplete specific stromal-tumor cell interaction(s) or perturb their molecular communications and assess the impact of these perturbations on the GRN controlling TS identity. Finally, we will assess whether pharmacological interventions targeting selected stromal-tumor communications can restrict tumor growth, metastasis or alleviate resistance to therapy." "Cell-cell cOmmuNicaTion As a driver of Cancer cell state identiTy - Decoding the impact of cell-cell communications on the identity of tumor states in skin cancers" "Chris Marine" "Laboratory for Molecular Cancer Biology (VIB-KU Leuven), Laboratory of Computational Biology (VIB-KU Leuven), IMEC-Interuniversitair Micro-Electronica, Université Libre de Bruxelles, Universiteit Gent" "Different tumor states (TS) exist within a given tumor with some cancer cells actively dividing, while othersdifferentiate, invade the surrounding tissues, give rise to metastasis, or are in a dormant and therapy-resilientstate. The identification of the intrinsic and extrinsic mechanisms that modulate TS diversity is essential for thedevelopment of new therapeutic strategies. In this project, we will dissect the mechanisms by which stromalcancercell communications influence the gene regulatory networks (GRNs), that defined TS identity in skincancers. We will take advantage of recent advances in single-cell lineage tracing, single-cell (spatial) multiomics,microfluidics and bio-informatics to map the spatial distribution of the different TS and their neighboringstromal cells, study how these cellular and molecular (e.g. ligand/receptor) interactions remodel the GRNs andepigenome of cancer cells and thereby regulate their specific TS identity. We will use dynamic models toassess how these interactions evolve during tumor progression, metastasis, and in response to therapy. Wewill reconstitute or deplete specific stromal-tumor cell interaction(s) or perturb their molecular communicationsand assess the impact of these perturbations on the GRN controlling TS identity. Finally, we will assesswhether pharmacological interventions targeting selected stromal-tumor communications can restrict tumorgrowth, metastasis or alleviate resistance to therapy." "Metabolic rewiring in cancer: Pharmacological targeting of serine/glycine synthesis addicted cancers" "Kim De Keersmaecker" "Microbial and Plant Genetics (CMPG), Laboratory for Disease Mechanisms in Cancer" "Metabolic rewiring is a well-established hallmark of cancer that supports tumor growth, survival and chemotherapy resistance. While normal cells often proliferate at slower rate than cancer cells and therefore have lower demands for serine and glycine, several cancer subtypes hyperactivate intracellular serine/glycine synthesis and become addicted to their own production. Examples of the latter include a significant subset of triple-negative breast cancers and T-cell acute lymphoblastic leukemias that are both currently treated with toxic intensive chemotherapy regimens. As such, this cancer-specific addiction offers an attractive drug target. Previously identified inhibitors of serine/glycine synthesis did not reach clinical trials, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. To address this need, we focused on drug repurposing with the aim to develop novel therapies that can rapidly enter the clinical practice as their safety and cost-effectiveness have been optimized before.A repurposing library was previously screened using a yeast-based model system that specifically upregulates serine/glycine synthesis as a tolerance mechanism against sublethal antifungal stress. Using this platform, we discovered two repurposed compounds, sertraline and thimerosal, that demonstrated selective toxicity to serine/glycine synthesis addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines, while they caused no growth impairment in cancer and normal lymphoid cell lines that take up serine and glycine from their environment. Furthermore, isotope tracer metabolomics, computational docking, enzymatic assays and drug-target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase (SHMT1/2) and phosphoglycerate dehydrogenase (PHGDH), respectively. In contrast to thimerosal, for which clinical applications are limited because of a toxic mercury group in its structure, sertraline is a widely used antidepressant and might therefore be a promising adjuvant therapeutic agent. Interestingly, we demonstrated that sertraline’s anti-proliferative activity was further enhanced by mitochondrial inhibitors, such as the antimalarial artemether. Moreover, combining sertraline and artemether caused G1-S cell cycle arrest in serine/glycine synthesis addicted breast cancer cells. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts.In conclusion, this research demonstrates that a yeast-based model system can be used as rapid and low-cost screening platform for compounds targeting serine/glycine synthesis. Furthermore, it provides molecular insights into the repurposed mode of action of the antidepressant sertraline and allows to delineate a group of cancers that is particularly sensitive to treatment with sertraline. Additionally, this work underscores the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a treatment strategy for serine/glycine synthesis addicted cancers, and confirms that doses of sertraline that are clinically used in the context of depression are sufficient to exert anticancer activity when used in combination therapy."