Abstract A007: Elucidating SEMA4D-YAP signaling in BBB transmigration of HER2+ Breast Cancer

Abstract Brain metastasis poses a challenge in cancer treatment due to its prevalence, diagnostic complexities, and the limited efficacy of systemic therapies due to the Blood Brain Barrier (BBB). Previous work in the lab established the first cohort of patient-derived Circulating Tumor Cells (CTCs) via ex vivo cultures. These CTCs were isolated from the peripheral blood of patients with metastatic luminal breast cancers to investigate the molecular features that allow a subset of CTCs to adapt and grow in the brain. This work identified Semaphorin 4D (SEMA4D), a transmembrane surface receptor of the Semaphorin family of receptors that regulate cell-cell interactions. SEMA4D has been identified to mediate BBB transmigration both in vitro and in vivo through its interaction with transmembrane receptor Plexin B1 (PLXNB1). Together with oncogene MYC, SEMA4D facilitates the colonization of the brain and promotes brain metastasis of CTCs. Despite these advances, the intracellular signaling mechanisms downstream of SEMA4D in cancer cells remain poorly understood. Transmembrane semaphorins can undergo bidirectional signaling: "forward signaling" through co-receptor binding and "reverse signaling" through their own cytoplasmic domains. While SEMA4D’s forward signaling via PLXNB1 has been well characterized, the functional contribution of SEMA4D’s reverse signaling for brain metastasis has not been investigated. In this study, we propose investigating the hypothesis that the reverse signaling via the cytoplasmic region of SEMA4D activates the Yes Associated Protein (YAP) pathway, facilitating BBB transmigration. Our data shows that truncating the cytoplasmic region of SEMA4D significantly reduces BBB transmigration of HER2+ breast cancer cells. This study will elucidate previously unknown reverse signaling mechanism in brain-tropic cancer cells and may reveal new therapeutic targets that address tumor cell transmigration in breast cancer. Citation Format: Anu D. Sunkara, Min Yu, Remi Klotz. Elucidating SEMA4D-YAP signaling in BBB transmigration of HER2+ Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A007.