Project description
Monitoring cancer-prone cells in human kidneys
Research shows that unique somatic mutation patterns can identify the origin of kidney cancer cells. Initial findings suggest that adaptation to low-oxygen conditions (hypoxia) may lead to increased mutations in kidney cells. The ERC-funded IDENTIKIT project will use a specific mutational signature to track cancer-prone cells in human kidneys. By monitoring these cells’ dynamics and studying their genome and transcriptome at a single-cell level, the project aims to uncover the causes of excessive mutations. It will use a non-invasive assay to detect these cells in urine samples, enabling longitudinal analysis of multiple donors without the need for biopsies. The project will also investigate whether hypoxia signalling, triggered by genetic factors or renal ischaemia, induces the kidney-specific mutational signature.
Objective
Understanding what makes our cells prone to develop cancer is key for identifying effective strategies of tumor prevention. By analyzing the genome of normal human cells, I obtained compelling evidence that the pattern of somatic mutations can be used to identify the cell-of-origin of kidney cancer. Although every cell accumulates somatic mutations during a lifetime, some are exposed to a specific mutational process that leave a detectable mark in their genome. Kidney cancers and their cell-of-origin show the same genetic mark, consisting of excess somatic point mutations with unique characteristics and unknown origin. We plan to use this mutational signature to track cancer-prone cells in human kidneys and a) follow their population dynamics; b) study their genome and transcriptome at a single cell level; c) understand the underlying causes of excessive mutation. Having already established a non-invasive assay to detect cancer-prone cells in urine samples, we can now analyse numerous donors, longitudinally and without biopsies. Our preliminary analyses point to adaptation to low-oxygen conditions (hypoxia) as the likely cause of excessive mutation in kidney cells and suggest defects in specific DNA repair pathways as a mechanism. We will test whether overactivation of hypoxia signalling, caused by either a genetic syndrome or exposure to renal ischemia, induces the kidney-specific mutational signature in humans. We will then dissect the molecular mechanism by functional experiments in vitro and in mouse models. Finally, we will test whether and how the diet contributes to the expansion of the mutation-prone cell subset in mouse kidneys. Overall, this study will provide unprecedented resolution of early events leading to kidney cancer initiation and will determine whether hypoxic stress is mutagenic and cancer-promoting. Further, this project will pursue the novel idea that cells can be tracked and possibly arrested before cancer initiation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics RNA transcriptomes
- natural sciences biological sciences genetics mutation
- medical and health sciences health sciences nutrition
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics genomes
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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20132 Milano
Italy
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