Analysis of Transcriptional Profiles During the Evolution of ccRCC from Premalignant to Malignant Lesions
Abstract
Background: Kidney cancer is the seventh most common cancer in the Western world and when it spreads it is usually incurable. Recent advances in chemotherapy for kidney cancer have proven disappointing, and so there is a pressing need for new therapeutic agents and to understand how best to employ current treatments. Most kidney cancers develop from normal kidney cells following inactivation of a tumour "brake" called VHL. This activates hundreds of responses that are normally brought about by a lack of oxygen reaching the cells. However, these responses have mixed effects, which paradoxically both promote and restrain tumour growth. In order to progress to fully fledged cancer, these cells have to rebalance these responses to favour those that promote tumour growth. How cells do this is currently poorly understood. Objective: A few patients develop kidney cancer as part of a hereditary disease (called VHL syndrome). Their kidneys often contain multiple tumours, as well as early precancerous lesions that have not yet re-balanced the responses that are required for tumours to grow. We will analyse tissue from these patients that is surgically resected during standard clinical care, using it to compare normal kidney cells, precancerous cells, and fully fledged kidney cancer cells. Characterising individual cells from these different lesions will allow us to track how these pathways adapt as healthy cells transform into cancer cells and then expand into tumours. This will provide unprecedented insight into how kidney cancers form. Innovation: The multiple precancerous lesions in kidneys of individuals with VHL syndrome provide a unique way of studying early kidney cancer development, which is often not possible for human cancer. Our studies will couple this with cutting-edge technology that will allow us, for the first time, to examine thousands of responses in tens of thousands of individual cells from these kidneys simultaneously. This will allow us to track how cells change during the different phases of kidney cancer development. Impact: This work will help us understand how oxygen-sensing responses are altered to promote tumour growth. In doing so, we aim to identify potential therapeutic targets that are specific to tumour-promoting responses. In addition, identifying responses that promote or restrain tumour development will allow us to classify tumours in to those that are likely to progress rapidly or more slowly, which will be useful in deciding how best to treat patients with existing treatments.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010491
Entities
People
- Olivia Lombardi
Organizations
- United States Army
- University of Oxford