Breast Cancer-derived PDGFB Remodels the CNS Vascular Niche to Promote Brain, Spinal and Leptomeningeal Metastasis
Year: 2026
Type: preprint
Abstract: Background: Central nervous system (CNS) metastases are a major driver of breast cancer (BC) mortality. Recently, our group demonstrated that platelet-derived growth factor-B (PDGFB) and its receptor, platelet-derived growth factor receptor-beta (PDGFRβ), promote BC metastasis to the brain; however, the cellular/molecular mechanisms driving this process remain unclear. Here, we investigated tumor-derived PDGFB effects on the CNS vascular niche in regulating metastatic spread. Methods: Triple-negative BC cells were engineered to overexpress PDGFB and used to evaluate endothelial sprouting, blood-brain barrier (BBB) function, vascular permeability and experimental CNS metastasis. A novel retro-orbital (RO) injection model was used to study leptomeningeal/spinal experimental metastasis. Results: , PDGFB increased CNS metastatic burden and altered tumor vasculature in xenograft and allograft models of BC. Furthermore, PDGFB promoted robust colonization of both spinal and leptomeningeal compartments, identifying a previously underappreciated role for this signaling pathway in a clinically devastating form of CNS metastasis. Analysis of patient transcriptomic datasets revealed enrichment of angiogenesis-related pathways in PDGFB-high tumors from patients who developed CNS metastases. Conclusions: Collectively, these findings identify tumor-derived PDGFB as a key regulator of CNS vascular remodeling and metastatic tropism, while introducing a new experimental framework to study spinal metastases and leptomeningeal disease in BC. Key Points: Tumor-derived PDGFB remodels the CNS vasculature and disrupts barrier integrityPDGFB promotes brain, spinal, and leptomeningeal metastasisRetro-orbital injections provide a new model of leptomeningeal and spinal metastasis. Importance of Study: Central nervous system (CNS) metastases are among the most lethal complications of breast cancer. Vascular cooption is recognized as a critical step in the metastatic cascade, but the tumor-derived signals which mediate this process are not fully understood. This study identifies PDGFB as a key signaling molecule which modulates the CNS endothelium, a previously underappreciated function. Beyond advancing our understanding of PDGFB-driven brain metastasis, this work also expands the role of PDGFB in promoting spinal and leptomeningeal metastasis. We establish a mechanistic framework connecting tumor-derived PDGFB to vascular dysfunction and CNS tropism, highlighting a potential opportunity to improve patient prognosis. Additionally, we employ a novel experimental model of leptomeningeal disease through retro-orbital (RO) injection of breast cancer cells. Together, these findings provide new insight into CNS metastasis while establishing experimental tools that may accelerate advancements in the understanding and treatment of brain, spinal, and leptomeningeal metastasis.
Authors: Nathaniel S. Grabinski, Jesse J. Reardon, Sajita Shah, Jonathan J. Adorno, Paul Lee, Rebecca L. Packard, Yalini Ramamoorthy, Katie A. Thies, Prathik A. Chakravarthy, Shashwat S. Agarwal, Jonathan M. Spehar, Tasneem A. Arsiwala, James W. Carpenter, Alexis A. Mossing, Johnathon G. Schiebel, Sarah A. Steck, Alexander J. Didier, Dillon S. Richardson, Luke Kollin, Monica Venere, Jonathan P. Godbout, Paul R. Lockman, Sasha Beyer, Kara N. Corps, Jessica O. Winter, Jonathan W. Song, Steven T. Sizemore, Gina M. Sizemore
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222584691