To obtain a deeper and more dynamic understanding of tumor aggressiveness and resistance mechanisms being influenced by the brain tumor microenvironment.
Glioblastoma is the most frequent and malignant type of brain cancer and most patients have a poor survival. Novel therapeutic strategies that overcome the efficient mechanisms of resistance are urgently needed. Our aim is to identify, understand and overcome mechanisms of resistance in the microenvironment of glioblastomas. The microenvironment is heterogenous leading to potentially different mechanisms of resistance in the core and periphery of glioblastomas. Adding to the complexity, there is a high frequency of non-tumor cells in glioblastomas leading to potential critical cross-talk between tumor cells, microglial cells and macrophages and other cell types. Having identified novel clinical relevant targets taking the interaction between tumor cells and the microenviroment into account, we can turn this knowledge against the glioblastoma from a therapeutic point-of-view.
Merits of the lab:
Our lab is at the cutting edge in the microenvironment field having the newest equipment. With our translational university-hospital profile and group members with both MD and MSc background, we use patient tissue for discovery and validation having the main goal to get back to the patients with therapeutic progress. In our research we have demonstrated that the microenvironment is critical for aggressiveness and recurrence of glioblastoma. We have also found that microglia-macrophages protect against chemotherapy and shorten patient survival and that genetic alterations influence microenvironment. Illustrating our leading position, we hosted and organized the last European Congress of Neuropathology.
Why do we want medical doctors?
We have both MDs and MScs in the group. Our MDs have had career paths in oncology, surgery and pathology. The group leader Bjarne Winther Kristensen is MD PhD, Clinical professor and senior consultant in neuropathology.
Glioblastoma is the most frequent and malignant brain tumor with 15.000 new cases per year in the EU. Standard of care includes surgery followed by radiation and temozolomide (TMZ) chemotherapy. Glioblastomas are characterized by extensive areas with hypoxia, peri-necrotic tumor cell palisades and microvascular proliferation, which are diagnostic hallmarks of glioblastoma (FIG 1, see later on). These aspects are part of the hypoxic niche in glioblastoma and have been associated with stem-like tumor cells and therapeutic resistance. In surgically removed glioblastoma tissue, a special type of immune cells called tumor-associated microglia and macrophages have been reported to constitute up to 30 % of the cells, a fraction that is even higher in hypoxic areas. These cells are capable of secreting cytokines, chemokines and growth factors, thereby influencing the microenvironment. However, their influence on tumor cell phenotype and therapy resistance – in a hypoxic microenvironment – has only been sparsely studied and is not understood. The overall aim of this project is to interrogate the microglial/macrophage and tumor cell phenotype in the hypoxic niche to understand this critical area more deeply and identify novel therapeutic targets.
How we will do it?
We will use “spatial profiling” to obtain both gene regulation data for cell clusters (up to 18.000 genes) and individual cells (up to 1000 genes) knowing at the same time exactly where the glioblastoma tumor cells and their neighbour cells are localized. We will do this with histological sections from glioblastoma tumor tissue from patients. This will give us the possibility to interrogate the tumor cell and microglial/macrophage phenotype and the cross-talk between them. Presence of target candidates involved in critical cross-talk will be validated at the protein level by immunofluorescence multiplexing using an independent set of glioblastoma biopsies. This will be followed by the functional investigation of the role of target candidates with patient tumor cell cultures established in our laboratory. Influence of knockdown on tumor cell growth and migration, chemoresistance and potentially angiogenesis will be investigated. To investigate the most promising targets, tumor cells will be injected into mice brains and growth monitored by MRI. Systemic treatment or local intra-tumoral injection with the therapy of interest will be given with and without combined treatment with the type of standard chemotherapy also given to patients.
Why is this important?
Novel therapeutic strategies taking into account that tumor cells are in fact intermingled with high numbers of macroglia/macrophages that influence the tumor cells may be key to therapeutic progress within the next decade. In the last decades, the major focus has primarily been on tumor cells alone. With the strategy in this project, we expect to identify novel, clinically relevant targets by taking the interactions between tumor cells, microglial/macrophage and microenvironment in the hypoxic niche into account. We can use this knowledge to guide the development of novel clinical trials in patients with glioblastomas, who all experience recurrence. The most promising targets are tested within the project in a pre-clinical mouse model and target selection is performed together with clinical collaborators leading the Department of Oncology/Phase 1 trial unit at Copenhagen University hospital selecting thereby the most translatable targets.
Who is a good fit for the project?
We seek an enthusiastic and self-motived new colleague who will actively contribute to the research in our group. Interest in oncology/tumor biology aiming to understand cross-talk between tumor cells and the other cells in the tumor – as well as an interest to make a difference for the patients – would be important. It would be good to have previous experience with laboratory work.
Previous experience with pathology, oncology, and neuroscience would be good but is not needed as such.
IDIBAPS#1 – Developing and investigating computing, machine learning and physiological modelling for understanding each individual heart towards personalised medicineDavid Brena2022-05-17T10:37:53+00:00