Abstract 4841: ZEB1 drives pro-metastatic membrane trafficking through upregulation of REEP2 in lung adenocarcinoma

Abstract Membrane trafficking governs the transport of proteins to intracellular and extracellular locations to maintain cell homeostasis. Although this process is frequently disrupted during cancer progression, the underlying mechanisms remain largely unknown. As a result, there are currently no effective drugs that target membrane trafficking. 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 in the tumor microenvironment (TME). 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. This screen identified REEP2, an endoplasmic reticulum (ER) shaping protein, as a novel regulator of EMT-dependent membrane trafficking. High REEP2 expression is associated with poor prognosis in LUAD patients, and REEP2 depletion decreases LUAD proliferation, migration, and invasion both in vitro and in vivo. REEP2 expression is positively correlated with expression of the EMT-driver, ZEB1, which is known to regulate gene expression via miRNA regulation. Our findings show that ZEB1 upregulates REEP2 expression by silencing miR-183 and miR-193a. Pro-metastatic secretion relies on the transport of cargo from the ER to the Golgi, and then to the plasma membrane. We discovered that REEP2 is necessary for colocalization of the ER exit site (ERES) protein SEC24D with the Golgi to facilitate cargo trafficking and ultimately drive secretion of pro-tumorigenic factors. This REEP2-driven secretome promotes cancer progression by increasing LUAD proliferation, migration, and immunosuppressive tumor microenvironment. Altogether, these findings establish REEP2 as a novel mediator of the EMT-driven pro-metastatic membrane trafficking program, revealing a specific vulnerability in mesenchymal LUAD. Citation Format: Kevin Fulp, Oluwafunminiyi Emmanuel Obaleye, Guan-Yu Xiao. ZEB1 drives pro-metastatic membrane trafficking through upregulation of REEP2 in lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4841.