Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
Rong Fu, … , Tao Lu, Zhao-Qiu Wu
Rong Fu, … , Tao Lu, Zhao-Qiu Wu
Published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1252-1270. https://doi.org/10.1172/JCI131507.
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Research Article Angiogenesis Therapeutics

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

Abstract

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.

Authors

Rong Fu, Yi Li, Nan Jiang, Bo-Xue Ren, Chen-Zi Zang, Li-Juan Liu, Wen-Cong Lv, Hong-Mei Li, Stephen Weiss, Zheng-Yu Li, Tao Lu, Zhao-Qiu Wu

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Figure 11

Treatment of Zeb1iΔEC mice with r.TGF-β1 protein recovers impaired tumor progression.

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Treatment of Zeb1iΔEC mice with r.TGF-β1 protein recovers impaired tumor...
(A) Immunoblot analysis of control (i.e., Ad–β-gal–infected) and ZEB1-deleted (i.e., Ad-Cre–infected) LLC tumor ECs that were treated with vehicle or 2 ng/mL r.TGF-β1 protein for 3 hours. (B) Immunofluorescent images showing p-SMAD2/3 (top) and SMAD2/3 (bottom) expression in the indicated cells as described in A. Nuclei, DAPI (blue). (C) Growth curves of LLC tumors grown for 21 days in Zeb1WT and Zeb1iΔEC mice that were treated with vehicle or 1.3 μg/kg r.TGF-β1 protein once every 3 days for a total of 3 times (5 mice each). (D) Gross images of freshly dissected tumors as described in C. (E and F) H&E-stained images (E) and quantification (F) of hemorrhagic necrosis in LLC tumors of vehicle- or r.TGF-β1–treated Zeb1WT and Zeb1iΔEC mice as described in C (5 mice each). Asterisks in E denote hemorrhagic foci. (G and H) Immunofluorescent images (G) and comparison (H) of metastasized cytokeratin+ LLC tumor cells in the inguinal LNs of tumor-bearing mice as described in C (5 mice each). The cytokeratin+ area is presented as a percentage of sectional area. All data are represented as mean ± SD. *P < 0.05; **P < 0.01. Differences were tested using 2-way ANOVA with Tukey’s post hoc test (C) and 1-way ANOVA with Tukey’s post hoc test (F and H).