Project Details
Projekt
Tracing cancer evolution and the metabolome: A cross-platform approach
Applicant
Dr. Othman Al-Sawaf
Subject Area
Hematology, Oncology
Term
from 2021 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 467697427
Cancerous cells acquire advantageous characteristics that grant them a survival advantage over non-cancerous cells. Genomic instability and genetic heterogeneity accelerate this evolutionary process, allowing the cancer cells to develop drug resistance. In an attempt to better characterize the processes underlying cancer evolution and the impact of genomic instability in cancer, the TRACERx study was initiated in 2014 in the UK. In this study, patients with non-small cell lung cancer (NSCLC) are tracked from initial diagnosis through treatment, possible relapses and death. Multi-region longitudinal tissue sampling and sequencing is performed in each patient to characterize cancer’s spatial and temporal evolution. The results from the first 100 patients enrolled in TRACERx have shown how subclonal driver mutations and chromosomal instability facilitate a seemingly unstoppable genetic diversification of cancer. The aim of this project is to focus on the cancer hallmark of dysregulated metabolism in the context of cancer evolution. Most of our knowledge on the metabolome of lung cancer is based on snapshots of metabolic states at certain timepoints of disease, but not on prospective longitudinal observations. We hypothesize that in patients with NSCLC, metabolic phenotypes and liabilities undergo dynamic changes as tumours evolve from an early-stage to metastatic disease. The first aim of this project will be to decipher alterations of metabolic pathways on a genomic and transcriptomic level; metabolite abundance will be measured with mass spectrometry in order to identify markers associated with disease stages. Using our knowledge on phylogenetic lineages of individual tumours, we aim to reconstruct the temporal order in which metabolic alterations occur. This will allow us to understand whether there are tumour metabolic dependencies that define metastatic clones and drive disease progression.One of the main causes of cancer related morbidity and mortality is cancer associate cachexia (CAC). This represents a state where cancer cells induce a systemic metabolic reprograming of the host with detrimental outcomes. This involves a debilitating loss of muscle mass (sarcopenia) and often loss of adipose tissue. Independent prognostic factors of cachexia are not well studied and the mechanism of the evolutionary dead end by which cancers “starve” the host to death is unclear. Approximately 40% of patients in TRACERx show signs of CAC. Hence, the second aim of this project is to use our cross-platform approach to identify mediators of catabolic stages and to discover metabolite biomarkers associated with CAC. This will allow us to identify patients who are at risk of developing CAC and develop future interventions to mitigate CAC development.In summary, this project aims to connect the dots between genomics, transcriptomics and metabolomics in order to decipher dynamics of cancer evolution and the metabolome in the context of NSCLC.
DFG Programme
WBP Fellowship
International Connection
United Kingdom
