Role of endothelium in tumor response to radiotherapy
BASIC DATA OF THE RESEARCH PROJECT
- ARRS code: J3-2529
- TITLE: Role of endothelium in tumor response to radiotherapy
- PROJECT LEADER: Res. Assoc., dr., Bostjan Markelc
- DURATION: 1.9.2020 - 31.8.2023
- APPLICANT RESEARCH ORGANISATION: INSTITUTE OF ONCOLOGY LJUBLJANA
- PARTICIPATING RESEARCH ORGANISATIONS: UNIVERSITY MEDICAL CENTRE LJUBLJANA, BIOTEHNICAL FACULTY
- FINANCING: Slovenian Research Agency
Although a majority of cancer patients will receive a course of radiation as part of their treatment, many of those patients will not be cured and will have a local recurrence of their cancer. Substantial improvements in the precision of the delivery of radiation have resulted in improved tumour control, but the doses of radiation are limited by deleterious effects on adjacent normal tissues. Another approach is to develop biological agents that can be used in concert with radiation. Recently, immunotherapies targeting immune checkpoints such as PD-1/PD-L1 and CTLA4 have been used in combination with radiotherapy, and although the results are promising, there are patients that do not respond favourably. Our goal here is to develop the biological underpinnings for such approaches focussing on the tumour vasculature.
Tumours are composed of cancer cells, extracellular matrix and host cells. Radiation therapy affects not only the cancer cells, but also the tumour microenvironment. However, the response of the tumour microenvironment, including the tumour vasculature is poorly understood. Another aspect when radiotherapy is used in treatment of cancer is the activation of endothelial cells. Although, endothelial activation after irradiation is often viewed as a detrimental pathological condition, it must be emphasized that endothelial cell activation draws immune cells to sites of infection or tissue injury. However, the principles of the crosstalk between the different immune cell populations and the irradiation activated tumour endothelial cells are still poorly understood.
Thus in this project we intend to develop strategies to enhance radiation therapy by delineating the vascular response to radiation with specific emphasis on blood flow and endothelial activation. Direct observation of the vasculature during and after irradiation with state of the art microscopic techniques combined with transgenic mouse models could resolve the effect of irradiation on blood flow, and how it is connected to tumour hypoxia. Moreover, the use of vasculature-on-a-chip model will allow robust testing of single parameters influencing the response of vasculature to irradiation, how this affects blood flow and the interactions of immune cells with endothelial cells. Coupled with detailed molecular analysis of the irradiated tumour samples from mice and patients, we intend to link the observed effects with their molecular origin. We aim to improve the understanding of the response of tumour blood vessels to radiotherapy by i) determining how structural changes of tumour vasculature after irradiation affect blood flow, ii) determining the timeline of changes in pathways involved in immune response in tumour endothelial cells after irradiation, and iii) determining the potential of targeting endothelial cells to increase homing of immune cells to tumours.
During this project we will establish the methodology for comparing data obtained from intravital imaging of tumour vasculature and blood flow to the data obtained from newly implemented murine vasculature-on-a-chip models. Further, a single cell and spatial transcriptome analysis of irradiated murine tumours and validation of the results in patient samples will provide a valuable dataset, which will be used to delineate the molecular origins of the observed changes. We will characterize the tumour vascular response, blood flow, and activation of endothelial cells and their perturbations after radiation. As the role of activated tumour endothelial cells after irradiation of tumours will be assessed, alterative means to combining immune checkpoint inhibitors in combination with radiation could be developed and tested.
Objective 1: Determine how structural changes of tumour vasculature after irradiation affect blood flow.
Objective 2: Determine the timeline of changes in pathways involved in immune response in tumour endothelial cells after irradiation.
Objective 3: Determine the potential of targeting endothelial cells to increase homing of immune cells to tumours.