Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies

• Published in: The Journal of clinical investigation Vol. 130; no. 3; pp. 1252 - 1270
• Main Authors: Fu, Rong, Li, Yi, Jiang, Nan, Ren, Bo-Xue, Zang, Chen-Zi, Liu, Li-Juan, Lv, Wen-Cong, Li, Hong-Mei, Weiss, Stephen, Li, Zheng-Yu, Lu, Tao, Wu, Zhao-Qiu
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-03-2020
• Subjects: Angiogenesis; Antibodies; Antineoplastic agents; Antitumor activity; Apoptosis; Biomedical research; Bone morphogenetic proteins; Cancer; Cancer diagnosis; Cancer metastasis; Cancer therapies; Cell death; Chemotherapy; Cisplatin; Development and progression; Drug delivery; Drug delivery systems; Endothelium; Evaluation; Females; Hypoxia; Immune checkpoint; Lung cancer; Metastases; Metastasis; PD-1 protein; Perfusion; Toxicity; Transcription factors; Transforming growth factors; Tumors; Zinc finger proteins; Angiogenesis; endothelial cells; Cancer immunotherapy; Therapeutics; Cancer
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci131507

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.