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Author ORCID Identifier

https://orcid.org/0009-0004-0545-7584

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 is frequently disrupted during cancer progression, and the underlying mechanisms remain largely unknown. Currently, no effective drugs target dysregulated membrane trafficking for cancer treatment. Recent evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma (LUAD) employs a membrane trafficking program to coordinate cancer cell invasion and immunosuppression. To further dissect the pro-tumorigenic membrane trafficking program, we initiated an in vivo CRISPRi screen to assess more than 2,000 membrane trafficking-related genes in a syngeneic mouse LUAD model. We identified REEP2, an endoplasmic reticulum (ER) shaping protein, as a novel regulator of EMT-driven membrane trafficking. High REEP2 expression is associated with poor prognosis in LUAD patients, and REEP2 depletion decreases LUAD cell proliferation and migration and suppresses tumor metastasis. We show that the EMT-activating transcription factor, ZEB1, upregulates REEP2 expression by silencing miR-183 and miR-193a. REEP2 is recruited to the ER exit sites and, in turn, facilitates the transportation of secretory cargoes from the ER to the Golgi. REEP2-dependent ER-to-Golgi trafficking machinery mediates the EMT-driven secretion of pro-tumorigenic factors that are required for LUAD metastasis. Altogether, these findings establish REEP2 as a novel nexus linking ER-to-Golgi trafficking machinery with EMT-dependent transcriptional network that underlies a vulnerability in EMT-driven cancers.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.221

Archival?

Archival

Funding Information

This study was supported by the National Institutes of Health Grant R00CA249048 from 2023 to 2026 and the National Institutes of Health Grant T32CA165990 from 2024 to 2026.

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