PhD Scientific Days 2024

Pathological and Oncological Sciences III.

Proteomic Study of Paired Primary Tumors and Brain Metastases from Lung Adenocarcinoma Patients Uncovers Distinct Phenotypes Linked to Survival

Text of the abstract

Introduction: Lung adenocarcinoma (LADC) is a disease with a high mortality rate, often due to the development of brain metastases, which significantly worsen prognosis.
Aims: As a follow-up to our pilot study (doi: 10.1016/j.esmoop.2022.100741), the aim of this work is to better understand tumor heterogeneity and disease progression by analyzing surgically removed primary tumors and brain metastases of LADC patients using proteomics.
Methods: Formalin-fixed, paraffin-embedded primary and brain tumor tissues from 58 patients were subjected to proteomic analysis using a previously established sample preparation protocol (doi: 10.1021/acs.jproteome.0c00850). Peptides were labeled with TMTpro 16-plex and the proteomic analysis was performed using high-performance liquid chromatography coupled with tandem mass spectrometry (Ultimate 3000 UPLC, QExactive HF-X). Protein identification and quantification were carried out using Proteome Discoverer 2.4 software. Statistical and bioinformatic analyses were conducted using R and Perseus software.
Results: Proteomic analysis resulted in the quantitation of 10,862 proteins, from which 7,418 proteins were quantified across all 116 samples. Primary tumors and brain metastases showed distinct protein expression profiles according to principal component analysis. In addition, four proteomic subtypes were detected by consensus clustering in both primary tumors and brain metastases, of which the primary subtypes showed an association with progression-free survival (PFS). The primary subtype with worse PFS was characterized by fast proliferation indicated by higher protein expression of Ki67 and Myc targets. In contrast, the subtype with the best PFS showed higher expression of immune-related genes. Downregulation of protective immune mechanisms was observed during the progression to brain metastasis. Notably, there was no significant relationship between the primary and metastasis subtype assignment within individual patients, suggesting a phenotype change.
Conclusion: Our results provide insight into the molecular heterogeneity of primary LADC tumors and their brain metastases, which may contribute to the development of new, personalized treatment strategies in the clinic.
Funding: Semmelweis 250+ Excellence PhD Scholarship (B.S.), 2021-1.2.4-TÉT-2021-00030 (B.D.)