Analyse von Krebsevolution und -metabolismus: Eine plattformübergreifende Studie
Zusammenfassung der Projektergebnisse
This project focused on cancer-associated cachexia (CAC) in non-small cell lung cancer (NSCLC) within the framework of the TRACERx study, a large-scale prospective project involving over 800 UK NSCLC patients. The TRACERx study tracks tumor evolution over time through longitudinal, multiregional sampling, providing insights into tumor genetics and progression from diagnosis to recurrence. This research aimed to identify genetic and phenotypic determinants of CAC using advanced methods, including AI-supported image analysis for body composition, whole-exome sequencing, and plasma proteomics. AI-assisted imaging was employed to monitor body composition changes- specifically in muscle and fat tissue - over time. Patients with significant weight loss, marked by CAC, exhibited significantly reduced survival compared to those with stable body composition. This association was validated in an external cohort from the Boston Lung Cancer Study. Genomic analyses uncovered distinctive features in CAC patients, notably amplifications in chromosome regions 11q22.3 and 3q27.1, associated with genes linked to muscle degradation and weight loss. RNA sequencing revealed increased expression of specific metalloproteinases and muscle-regulating genes, alongside activated inflammatory pathways, epithelial-mesenchymal transition, and hedgehog signaling. Immune profiling showed a higher proportion of neutrophils and a reduced number of T-cells in CAC tumors. The proteomic analysis highlighted elevated levels of GDF15, a stress hormone associated with reduced appetite and weight loss, particularly at disease recurrence when cachexia is most pronounced. Importantly, this hormone did not originate directly from tumors, suggesting systemic effects. GDF15’s role in CAC was further validated in mouse models, where a monoclonal antibody against GDF15 improved food intake and reversed cachexia symptoms, demonstrating therapeutic promise. Lastly, metabolomic profiling of plasma samples identified potential biomarkers, such as myoinositol, predictive of CAC development. This extensive integration of multiomic data in TRACERx has offered valuable insights into CAC pathophysiology, suggesting molecular targets and biomarkers for early detection and intervention, and highlights the need for further research on CAC across diverse cancer types.
Projektbezogene Publikationen (Auswahl)
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Body composition and lung cancer-associated cachexia in TRACERx. Nature Medicine, 29(4), 846-858.
Al-Sawaf, Othman; Weiss, Jakob; Skrzypski, Marcin; Lam, Jie Min; Karasaki, Takahiro; Zambrana, Francisco; Kidd, Andrew C.; Frankell, Alexander M.; Watkins, Thomas B. K.; Martínez-Ruiz, Carlos; Puttick, Clare; Black, James R. M.; Huebner, Ariana; Al Bakir, Maise; Sokač, Mateo; Collins, Susie; Veeriah, Selvaraju; Magno, Neil; Naceur-Lombardelli, Cristina ... & Swanton, Charles
