DEFB1 Identified as a New Driver of Lung Adenocarcinoma Growth, Offering Hope for Therapeutic Development
1. Uncovering the Hidden Enemy: DEFB1
Lung adenocarcinoma accounts for a substantial proportion of cancer‑related deaths worldwide, making the identification of fundamental drivers of tumor growth critically important. Existing therapies have limited capacity to fully suppress the persistent proliferation and metastasis of cancer cells. To discover core oncogenic drivers, the research team performed a genome‑wide CRISPR screening that systematically interrogated the entire genome.
2. Big‑Data Validation of a Key Cancer Driver
Combined in‑vitro experiments and mouse models identified the gene DEFB1 as a principal promoter of lung adenocarcinoma growth. By leveraging thousands of patient datasets (TCGA, GEO) and single‑cell analysis, the investigators demonstrated that DEFB1 is markedly overexpressed in tumor cells and constitutes a decisive factor that reduces patient survival.
3. Dual‑Target Mechanism: Metastasis Induction and Immune Modulation
DEFB1 drives tumor progression through two lethal mechanisms. First, it binds to the Periplakin (PPL) protein, triggering epithelial‑to‑mesenchymal transition (EMT) and facilitating cellular dissemination. Second, interaction with macrophage migration inhibitory factor (MIF) promotes polarization toward M2 macrophages, thereby protecting tumor cells from immune attack. To counteract these effects, the team engineered a potent monoclonal antibody, mAb‑5, which effectively suppressed tumor growth.
4. Future Implications
The discovery provides a clear therapeutic target—DEFB1—for patients with historically hard‑to‑treat lung adenocarcinoma. Given the favorable safety and efficacy profile of the antibody therapy, clinical trials are anticipated to deliver a novel, personalized treatment option for lung adenocarcinoma patients in the near future.
Lung adenocarcinoma, one of the most prevalent malignancies, underscores the urgency of identifying genes linked to its proliferation and prognosis for developing targeted therapies. In this study, we performed genome-wide CRISPR/Cas9 screening both in vitro and in vivo, and subsequently cross-referenced the findings with prognosis-related genes in lung adenocarcinoma. The screening results revealed that DEFB1 promotes lung adenocarcinoma proliferation, while our integrated analysis of single-cell sequencing, multiplex immunohistochemistry, TCGA, and GEO data concurrently demonstrated elevated DEFB1 expression in cancer cells, along with a negative correlation between DEFB1 expression and patient survival. Subsequently, functional studies employing DEFB1 knockout cells, re-expressed DEFB1 cells, and knockout cells supplemented with exogenous DEFB1 revealed that DEFB1 significantly enhances cell proliferation, migration, and invasion. Co-immunoprecipitation combined with mass spectrometry experiments was performed to uncover the mechanism of DEFB1, demonstrating that it interacts with Periplakin (PPL) to induce epithelial-to-mesenchymal transition (EMT) and proliferation, while simultaneously binding to Macrophage Migration Inhibitory Factor (MIF) to enhance M2 macrophage polarization. Furthermore, we developed multiple anti-DEFB1 monoclonal antibodies and found one of them, mAb-5, potently blocked DEFB1's function and inhibited lung adenocarcinoma progression in cell lines, organoids, xenografts, and spontaneous lung cancer models, while maintaining a favorable safety profile. Overall, our study identifies DEFB1 as a novel driver of lung adenocarcinoma, and the anti-DEFB1 monoclonal antibody mAb-5 emerges as a promising therapeutic candidate with significant potential.
We identified a novel causative gene for lung cancer—the leading cause of cancer mortality worldwide—and developed an antibody that directly neutralizes it. Patients suffering from drug resistance or metastasis can receive precision therapy tailored to their genetic profile, enabling them to remain healthier and spend more time with their loved ones.