Adaption and Escape
Targeting metabolic cancer cell plasticity to overcome escape from radiotherapy
Host: Universitätsklinikum Essen
Contact person: firstname.lastname@example.org / email@example.com
Location: Essen, Germany
Hypoxia is a common feature of human solid tumors and is considered as one main biological factor promoting tumor cell resistance to radiotherapy. Others and we revealed that chronic intermittent hypoxia acts as an important driver of adaptive changes that allow the cancer cells to survive these highly adverse conditions and promote tumor heterogeneity. A hypoxia/reoxygenation-induced metabolic reprogramming allowed the cancer cells to meet their bioenergetic and metabolic demands for sustained proliferation and survival after exposure to ionizing radiation. But the contribution of the genetic background to the metabolic response to radiotherapy and of the tumor cell intrinsic or induced metabolic plasticity to the escape of the cancer cells from radiotherapy remain to be defined.
The proposed project will profile metabolic demands of cancer cells with distinct genetic backgrounds upon exposure to ionizing radiation under diverse environmental conditions. Novel therapeutic strategies for overcoming intrinsic and acquired mechanisms for metabolic escape from radiotherapy will be defined and marker constellations for individualization of cancer radiotherapy will be predicted and validated in vitro and in vivo.
Metabolic control of metastases in irradiated breast cancer
Host: Université catholique de Louvain
Contact person: firstname.lastname@example.org
Location: Louvain, Belgium
Defects of mitochondrial function have long been suspected to contribute to the development and progression of cancer. Mitochondria besides their roles as powerhouses and biosynthetic hubs are a main source of ROS. Indeed, the maintenance of the mitochondrial potential by means of electron transfer chain (ETC) during respiration produces superoxide as a main byproduct. In cancer cells, it has been reported that natural occurrence of mutations partially impairing ETC complex I and identification of an unprecedented phenotype corresponding to TCA cycle overload promote mtROS-dependent tumor metastasis. In this context, we recently found that several chemotherapies, including doxorubicin and cisplatin, promote ROS production and ROS-induced breast cancer cell migration and metastasis. On the other hand, in another tumor type, we also found that radiotherapy increases cancer cell respiration and promotes a morphological change evoking an epithelial-to-mesenchymal transition (EMT). Here, we will thus investigate whether X-ray radiotherapy promote breast cancer cell EMT, migration, invasion and metastasis.
This project will increase the understanding how radiotherapy promotes the metastatic potential of cancer cells and how mitochondria-targeted anti-oxidants or other metabolic targets might reverse this phenotype.
Key proteins of the cancer cell adhesome connecting radiosensitivity and angiogenesis
Host: Technische Universität Dresden
Contact person: email@example.com
Location: Dresden, Germany
The cancer cell adhesome consists of cell adhesion molecules (CAMs), growth factor receptors (GFR), adapter and signaling proteins, which mutually and cooperatively interact. The impact of these tightly regulated CAM/GFR interactions has not been described for the interrelation between cellular radiosensitivity and cancer cell-induced angiogenesis. Using the area vasculosa model of the chicken embryo, we aim at systematically investigating (i) the spatio-temporal relation between the sprouting of new vessels through cancer cell secreted growth factors in dependence on adhesome proteins as well as (ii) the cancer cell radiosensitivity at different stages of the angiogenic process in dependence on adhesome proteins.
Using a high throughput RNAi screen, novel cancer cell adhesome molecules influencing vessel induction, tumor growth and radiosensitivity will be established. These candidates will be subjected to more in-depth analyses to unravel the underlying molecular mechanisms and the therapeutic exploitability.
Molecular and cellular consequences of FLASH radiotherapy on metastatic potential
Host: Institut Curie Paris
Contact person: firstname.lastname@example.org
Location: Paris, France
Medulloblastoma (MB) is a highly invasive pediatric tumor of the cerebellum. Despite a better cure rate due to multimodal treatments that associate chemotherapy, surgery and radiotherapy (RT), 20-30% of the children are incurable. Moreover, survivors suffer from important side effects. Transcriptomic analyses have defined 4 molecular subgroups of MB. Among them, the group 3 which represents 25% of the patients is the most problematic at the clinical level. This subgroup is metastatic and resistant to all the current therapies. The 20 to 30% of patients that die from a MB essentially display a group 3 MB. At the molecular level, this subgroup is poorly characterized although we recently showed that it is driven by an abnormal identity unrelated to the cerebellum (Garancher et al., Cancer cell 2018). Since RT is central in MB treatment and that group 3 MB frequently relapse, the aim of our project is to study the mechanism by which Group 3 MB escape to RT. To that end, we will use different in vitro and in vivo models, such as MB cell lines, human patient-derived medulloblastoma (PDX) and primary mouse cerebellar progenitors modified by transduction (oncogene expression or KD (sh-CRISPR) of tumor suppressors). We will study their response to RT both in vitro but, more importantly, in vivo following orthopically grafting into the cerebellum of mice by stereotaxis. First, a targeted approach will be performed to investigate of the activation of p53 pathway and its role since, surprisingly, Group 3 MB keeps an intact WT TP53 gene. An unbiased approach by RNAseq will be next also undertaken. Clonal selection will be also investigated by barcoding and single-cell RNAseq and an unbiased CRISPR screen will be performed to investigate the mechanism of resistance.
Subcellular Targeting of Radiosensitizers and Radionuclides to Enhance Radiotherapy
Host: University of Oxford
Contact person: email@example.com
Location: Oxford, United Kingdom
The capacity of pharmaceutical agents to selectively find their biological targets is an important determinant of their usefulness in clinical medicine. Many pharmaceutics are directed against intracellular targets that reside in organelles. Carriers that selectively target these subcellular structures have been investigated, and include nanoparticulate drug carriers, chemically modified proteins and deoxyribonucleotide-based agents. As well as the nucleus, the mitochondria, endoplasmic reticulum, Golgi-complex, the lysosomal system have all been investigated as intracellular targets of irradiation. There is increasing evidence that the nucleolus, the site of ribosomal assembly, plays an important role in sensing and orchestrating the response to cellular stresses including that which occurs in response to radiation. Therapeutic strategies that specifically hamper nucleolar function are being investigated in cancer and may be particularly effective in combination with radiotherapy. The initial central aim of this project will be to develop nucleolar-targeting oligonucleotide-based agents aimed at causing nucleolar functional disruption and radiosensitisation. Direct delivery of radiation to nucleolar sites using oligonucleotide-based radionuclide-labelled compounds will also be tested.