Myeloid-Derived Growth Factor-Regulated Oncogenesis in Lung Adenocarcinoma Is Associated with EGFR Status and Cancer Aggressiveness

Epidermal growth
factor receptor (EGFR) tyrosine kinase
inhibitors
have transformed lung adenocarcinoma (LUAD) treatment in EGFR-mutant
(MT) patients, but strategies targeting wild-type (WT) EGFR tumors
remain necessary. This study analyzed a diverse LUAD patient cohort
with EGFR mutation statuses and wild-type profiles for ALK and KRAS
to identify stage-specific biomarkers. Using quantitative proteomics
and multiomics, we discovered 21 dysregulated proteins in early-stage
EGFR-WT LUAD, identifying myeloid-derived growth factor (MYDGF) as
a key candidate biomarker. Elevated MYDGF levels in tissue (n = 117) and serum (n = 196) correlated
significantly with cancer stage in EGFR-WT patients but not EGFR-MT
cases. Notably, a higher tumor-to-normal MYDGF ratio predicted a favorable
prognosis in early-stage EGFR-WT LUAD. Functional studies demonstrated
that MYDGF exerts distinct roles in cell viability and migration depending
on its cellular localization and the invasive potential of cancer
cells. Specifically, secreted MYDGF promoted a protumorigenic phenotype,
whereas excess intracellular MYDGF appeared to suppress the oncogenic
capacity of aggressive cancer cells. MYDGF knockdown and subsequent
proteomic analysis provided further insights into these context-dependent
functions. These findings highlight EGFR status- and stage-specific
proteomic profiles in LUAD, emphasizing the importance of context-dependent
biomarker assessment for personalized treatment strategies.