Investigating Molecular Heterogenecity in Lung Cancer Using Proteomic and Bioinformatic Approaches
Szeitz Beáta
Pathological and Oncological Divison
Dr. Matolcsy András
SE Belgyógyászati és Onkológiai Klinika tanterme
2024-10-10 14:00:00
Diagnostic, Digital and Molecular Pathology
Dr. Kiss András
Dr. Szász Marcell
Dr. Dezső Katalin
Dr. Spisák Sándor
Dr. Kovalszky Ilona
Dr. Tóvári József
Dr. Varga János Tamás
Advances in omics profiling have enhanced our understanding of lung cancer, revealing new molecular subgroups and new avenues in targeted therapies. Proteomics, in particular, can bring new insights into cancer by offering a closer representation of the phenotype. In our work, we aimed to perform a proteomic analysis complemented with gene expression data on relatively rare lung cancer types to gather insights on their intra- and intertumoral heterogeneity.
In the small cell lung cancer (SCLC) study, we focused on characterizing newly defined SCLC subtypes at the protein level. We examined pellets and cell media of 26 human SCLC cell lines, supplemented with public transcriptomic data of SCLC cell lines and tissues. We confirmed the presence of molecular subtypes at protein level which were previously defined based on the gene expression of key transcription regulators: ASCL1, NEUROD1, POU2F3, and YAP1. We identified proteins with potential subtype-specific expression, including known druggable proteins and potential blood-based markers, and pathways that may be uniquely activated or suppressed in a certain subtype compared to the other three subtypes, representing further potential therapeutic targets. Importantly, while tissue-based immunohistochemistry studies failed to confirm a YAP1-driven subtype, we found it to be the most distinct SCLC subgroup.
In the study of ALK-rearranged lung adenocarcinoma (LADC), we performed, for the first time, spatial transcriptomic (NanoString GeoMx, 12 regions per case) and proteomic profiling (2-6 regions per case) on seven treatment-naïve formalin-fixed paraffin-embedded tumors with varying histopathological features. The two molecular layers exhibited modest correlation with each other, however, both datasets demonstrated stronger intertumoral heterogeneity compared to intratumoral heterogeneity. We identified potential markers and dysregulated pathways linked to tumors and normal adjacent tissues, and to the extent of immune infiltration, mucin and stroma content, including markers that behave distinctively in ALK-rearranged LADCs compared to non-ALK-driven LADCs. The extracellular matrix elements, particularly fibronectin 1, exhibited substantial variability within tumors.
In summary, the studies presented in this thesis generated new hypotheses for future lung cancer research, providing a list of biomarkers and dysregulated pathways with potential clinical relevance, and contributed to our understanding of cancer biology.
