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Author ORCID Identifier

https://orcid.org/0000-0001-6241-0652

Date Available

5-1-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Guan-Yu Xiao

Faculty

Christine Brainson

Faculty

Yekaterina Zaytseva

Abstract

Membrane trafficking plays a critical role in cellular function and is frequently dysregulated in cancer to promote metastasis. In lung adenocarcinoma (LUAD), the epithelial-to-mesenchymal transition (EMT) activating transcription factor, ZEB1, drives a pro-metastatic membrane trafficking program; however, the underlying molecular mechanisms remain poorly understood. Using a CRISPR interference (CRISPRi) in vivo screen of 2,099 membrane trafficking regulators in a syngeneic mouse model of EMT-driven LUAD, we identified REEP2 — an endoplasmic reticulum (ER) shaping protein — as a critical regulator of tumor progression. REEP2 mRNA expression correlates with poor prognosis, EMT signatures, and an immunosuppressive tumor microenvironment in LUAD patients. Here, we found that ZEB1 transcriptionally upregulates REEP2, which enhances endoplasmic reticulum (ER)-to-Golgi trafficking and drives the secretion of pro-tumorigenic and immunosuppressive factors. REEP2 depletion suppresses LUAD cell proliferation, cycle progression, and invasive capacity in vitro, and reactivates anti-tumor immunity to inhibit tumor growth and metastasis in vivo. These findings reveal a novel ZEB1–REEP2 axis that couples EMT to a pro-metastatic secretory program and identify REEP2 as a promising therapeutic target in metastatic LUAD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.220

Archival?

Archival

Funding Information

This study was supported by the National Institutes of Health Grant R00CA249048 from 2023 to 2026.

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