Abstract 5137: Epithelial-to-mesenchymal transition coordinates REEP2 to drive pro-metastatic membrane trafficking program in lung cancer

Abstract Membrane trafficking governs the transport of molecules to both intracellular and extracellular locations, thereby maintaining cell homeostasis. During cancer progression, alterations in membrane trafficking are frequently observed. Nevertheless, no effective drugs target membrane trafficking currently and the many mechanisms underlying the dysregulation of membrane trafficking in cancer progression remain a significant unresolved question. Our recent research discovered that the epithelial-to-mesenchymal transition (EMT) employs a membrane trafficking program to coordinate cancer cell invasion and immunosuppression in the tumor microenvironment (TME) in lung adenocarcinoma (LUAD). Importantly, blocking the EMT-driven membrane trafficking program re-sensitizes LUAD to immune checkpoint inhibition, suggesting significant therapeutic potential for this pathway. To dissect the pro-metastatic membrane trafficking program, we initiated a CRISPRi in vivo screen to assess more than 2, 000 trafficking-related genes in syngeneic mouse LUAD models for their requirements for tumorigenesis. Our preliminary studies identified REEP2 as a novel regulator of the EMT-dependent membrane trafficking program, which is linked to poor prognosis and an immunosuppressive TME in LUAD patients. Our findings here show that the EMT-activating transcription factor ZEB1 upregulates REEP2 by relieving its silencing mediated by miR-193a, thereby facilitating endoplasmic reticulum (ER) polarization to the Golgi apparatus. The REEP2-driven ER polarization promotes pro-metastatic secretory trafficking. Blockade of REEP2 suppresses LUAD cell proliferation, migration, invasion in vitro, and tumor metastasis in the syngeneic LUAD mouse tumor model. Our findings elucidate the molecular mechanisms underlying LUAD metastasis and support the development of REEP2 inhibitors to prevent EMT-driven cancer metastasis. Citation Format: Kevin Fulp, Oluwafunminiyi Obaleye, Guan-Yu Xiao. Epithelial-to-mesenchymal transition coordinates REEP2 to drive pro-metastatic membrane trafficking program in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5137.