# DCBLD1 Promotes Lung Tumorigenesis by Inhibiting PTP1B Dephosphorylation of EGFR

## TL;DR

DCBLD1 promotes lung cancer by preventing the deactivation of EGFR, leading to sustained cancer signaling and tumor growth.

## Contribution

DCBLD1 is identified as a novel LUAD risk gene that promotes tumorigenesis by inhibiting PTP1B-mediated EGFR dephosphorylation.

## Key findings

- DCBLD1 overexpression promotes cellular transformation in bronchial epithelial cells and organoids.
- DCBLD1 deficiency in mice significantly suppresses LUAD initiation.
- DCBLD1 knockdown shows antitumor effects in organoid and xenograft models.

## Abstract

Lung adenocarcinoma (LUAD) progression involves multistep molecular pathogenesis, with many critical mediators of malignant transformation yet to be fully characterized. Building upon our previous discovery of discoidin, CUB and LCCL domain containing 1 (DCBLD1) as a novel LUAD risk-associated gene, we systematically investigated its function and underlying mechanisms in LUAD. Intriguingly, DCBLD1 overexpression promotes cellular transformation in both bronchial epithelial cells and EGFRL858R alveolar type II organoids, while its deficiency in DCBLD1-/- mice significantly suppresses LUAD initiation. Mechanistic studies revealed that DCBLD1 drives oncogenesis through direct interaction with EGFR. Specifically, the intracellular domain of DCBLD1 competitively binds to EGFR, displacing the critical negative regulator PTP1B phosphatase. This displacement impairs EGFR dephosphorylation, leading to sustained receptor activation and subsequent hyperactivation of downstream PI3K/AKT and MAPK signaling cascades. The sustained signaling activation produces significant clinical implications for LUAD treatment. In therapeutic studies, DCBLD1 knockdown demonstrated substantial antitumor effects in both patient-derived organoid and xenograft models, independent of EGFR mutation status. These findings position DCBLD1 as a promising therapeutic target for LUAD patients, offering a potential strategy that complements current EGFR mutation-based approaches.