Faculty, Staff and Student Publications

Language

English

Publication Date

2-2-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI198418

PMID

41364502

PMCID

PMC12867136

PubMedCentral® Posted Date

12-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist osimertinib (Osi) eventually relapse, owing in part to the emergence of drug-tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intratumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell lines in which drug-naive (DN) cells were rendered OR by chronic exposure to escalating doses of Osi. Cocultured in vitro or coinjected into mice, paracrine signals from OR cells enhanced the growth and metastatic properties of DN cells. EMT and senescence-activated nonoverlapping secretomes, and OR cells governed DN cells by undergoing EMT but not senescence. Mechanistically, Osi rapidly increased TGF-β2 levels to initiate EMT, which triggered a Golgi remodeling process that accelerated the biogenesis and anterograde trafficking of secretory vesicles. The protumorigenic activity of OR cells was diminished by depletion of EMT-dependent secreted proteins or the EMT-activating transcription factor ZEB1. These findings identify paracrine mechanisms by which OR cells drive LUAD progression.

Keywords

Acrylamides, Humans, Aniline Compounds, Lung Neoplasms, Animals, Adenocarcinoma of Lung, Mice, Cell Line, Tumor, Transforming Growth Factor beta2, Epithelial-Mesenchymal Transition, Disease Progression, Neoplasm Proteins, ErbB Receptors, Paracrine Communication, Indoles, Pyrimidines, Cell biology, Clinical Research, Oncology, Cancer, Drug therapy, Oncogenes

Published Open-Access

yes

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