Lung cancer metabolism : from molecular mechanisms to translational studies

Cancer cells rewire their metabolism to sustain rapid proliferation, enhance survival, and evade therapeutic intervention. Deubiquitinating enzymes (DUBs) play a crucial role in regulating growth-related pathways by modulating protein stability and activity, yet their specific contributions to non-small cell lung cancer (NSCLC) remain largely unexplored. This thesis identified USP9x and USP39 as novel metabolic regulators in NSCLC. USP9x was found to deubiquitinate PYCR3, linking it to the proline cycle, while USP39 regulates mitochondrial metabolism by controlling PDHA, a component of the pyruvate dehydrogenase (PDH) complex. These findings expand our understanding of DUB-mediated metabolic control and suggest new potential therapeutic targets. In parallel, this thesis explored novel biomarker candidates for lung adenocarcinoma (LUAD) diagnosis through transcriptomics and metabolomics. Using machine learning, a 30-gene signature was identified that differentiates LUAD from a non-LUAD control group, including other lung cancers, benign and metastatic lesions, with high diagnostic performance. Additionally, metabolic profiling of tissue and plasma samples revealed pyrraline and phenol sulfate as potential biomarkers, raising the possibility of a minimally invasive diagnostic approach. While these findings provide exciting insights into lung cancer metabolism and diagnosis, limitations such as small sample size necessitate further validation in larger, independent cohorts. Future research should focus on confirming the clinical utility of these biomarkers and exploring the therapeutic relevance of DUB inhibition in lung cancer. By integrating functional studies and multi-omics approaches, this thesis contributes to deeper understanding of LUAD pathogenesis and paves the way for improved diagnostic and therapeutic approaches.

List of scientific papers

I. Becirovic T, Zhang B, Lindskog C, Norberg E, Vakifahmetoglu-Norberg H, Kaminskyy VO, and Kochetkova E. Deubiquitinase USP9x regulates the proline biosynthesis pathway in non-small cell lung cancer. Cell Death Discov. 2024;10(1):342.
https://doi.org/10.1038/s41420-024-02111-2

II. Becirovic T, Zhang B, Vakifahmetoglu-Norberg H, Kaminskyy VO, Kochetkova E, and Norberg E. USP39 regulates pyruvate handling in non-small cell lung cancer. Cell Death Discov. 2024;10(1):502.
https://doi.org/10.1038/s41420-024-02264-0

III. Becirovic T, Zhang B, Kochetkova E, Kas Elyas K, Talanti A, Grozman V, Nyrén S, Kamali C, Kaminskyy VO, Vakifahmetoglu-Norberg H, Hydbring P, Ekman S, and Norberg E. Integrative Transcriptomics and Meta- bolomics Analysis of Tumors and Plasma Identifies a Unique Gene Signature and Metabolites for the diagnosis of Lung Adenocarcinoma. [Submitted]