Novel therapeutic approaches to target cancer spread in the brain
Lead Research Organisation:
King's College London
Department Name: Imaging & Biomedical Engineering
Abstract
Strategic Research Priority: Bioscience for Health
Abstract
Several foreign cell types have the intrinsic propensity to cross the mammalian blood-brain barrier and establish themselves in the brain causing various types of disease. We propose to study the mechanisms of cell migration and tissue invasion of human cells foreign to the brain in this context. As research models we will use metastatic breast cancer and melanoma cells in organotypic brain cultures and live animals. Using various cell biological, biochemical and genetic strategies combined with diverse imaging approaches, we will study which cellular mechanisms are most important for disease-relevant cell migration and spread in the brain.
Project
Our groups study cell migration in its 'native' environment, i.e. ex vivo in live organotypic cultures and live animals, to improve the understanding of its underlying mechanisms. The actin cytoskeleton regulates many cellular processes, primarily by providing the mechanical forces necessary for cellular shape change and therefore is essential for cell migration and invasion, both critical determinants during development and disease. For this project, we chose the context of brain metastasis as it is a major reason for extremely poor prognosis and mortality in cancer patients with limited therapeutic options. Brain metastasis is often characterized by fast spread and outgrowth, and is very frequent in breast cancer and melanoma. Little is known how and to what preferred locations metastasizing tumour cells spread in the brain after crossing the blood-brain-barrier.
We propose to study the mechanisms of cell migration and tissue invasion of metastatic breast cancer and melanoma within the brain. In particular, we will disturb actin contractility and the cytokine environment in a controlled manner.
Objective1. Setup of breast cancer and melanoma organotypic invasion assays in different models of the brain microenvironment; (rotation project and year1) using time-lapse fluorescence microscopy and complex matrices.
Objective2. We will test a battery of inhibitors to interfere with cancer cell migration/invasion in the brain microenvironment (year1-2) and validate mechanistic findings by gene knock down strategies in vitro and ex vivo (year2).
Objective3. Application of an in vivo mouse model of breast cancer and/or melanoma brain metastasis (year2) for tracking and quantification of metastatic spread and lesion outgrowth using multi-modal imaging (SPECT-CT-fluorescence,(2)). Mechanistic data obtained in vitro and ex vivo will be tested in this pre-clinical model (year3).
The candidate will obtain multi-disciplinary experience cell biology, biochemistry, animal models and imaging, and benefit from being embedded into Comprehensive Cancer Imaging Centre-KCL&UCL and the Randall Division.
Abstract
Several foreign cell types have the intrinsic propensity to cross the mammalian blood-brain barrier and establish themselves in the brain causing various types of disease. We propose to study the mechanisms of cell migration and tissue invasion of human cells foreign to the brain in this context. As research models we will use metastatic breast cancer and melanoma cells in organotypic brain cultures and live animals. Using various cell biological, biochemical and genetic strategies combined with diverse imaging approaches, we will study which cellular mechanisms are most important for disease-relevant cell migration and spread in the brain.
Project
Our groups study cell migration in its 'native' environment, i.e. ex vivo in live organotypic cultures and live animals, to improve the understanding of its underlying mechanisms. The actin cytoskeleton regulates many cellular processes, primarily by providing the mechanical forces necessary for cellular shape change and therefore is essential for cell migration and invasion, both critical determinants during development and disease. For this project, we chose the context of brain metastasis as it is a major reason for extremely poor prognosis and mortality in cancer patients with limited therapeutic options. Brain metastasis is often characterized by fast spread and outgrowth, and is very frequent in breast cancer and melanoma. Little is known how and to what preferred locations metastasizing tumour cells spread in the brain after crossing the blood-brain-barrier.
We propose to study the mechanisms of cell migration and tissue invasion of metastatic breast cancer and melanoma within the brain. In particular, we will disturb actin contractility and the cytokine environment in a controlled manner.
Objective1. Setup of breast cancer and melanoma organotypic invasion assays in different models of the brain microenvironment; (rotation project and year1) using time-lapse fluorescence microscopy and complex matrices.
Objective2. We will test a battery of inhibitors to interfere with cancer cell migration/invasion in the brain microenvironment (year1-2) and validate mechanistic findings by gene knock down strategies in vitro and ex vivo (year2).
Objective3. Application of an in vivo mouse model of breast cancer and/or melanoma brain metastasis (year2) for tracking and quantification of metastatic spread and lesion outgrowth using multi-modal imaging (SPECT-CT-fluorescence,(2)). Mechanistic data obtained in vitro and ex vivo will be tested in this pre-clinical model (year3).
The candidate will obtain multi-disciplinary experience cell biology, biochemistry, animal models and imaging, and benefit from being embedded into Comprehensive Cancer Imaging Centre-KCL&UCL and the Randall Division.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009513/1 | 01/10/2015 | 31/03/2024 | |||
| 1628774 | Studentship | BB/M009513/1 | 01/10/2015 | 31/12/2019 | Laura Stennett |