Brain metastasis-associated fibroblasts secrete fucosylated PVR/CD155 that induces breast cancer invasion
Emma Adhikari,
Qian Liu,
Joseph Johnson,
Paul Stewart,
Viktoriya Marusyk,
Bin Fang,
Victoria Izumi,
Kiah Bowers,
Kelly M. Guzman,
John M. Koomen,
Andriy Marusyk,
Eric K. Lau
Affiliations
Emma Adhikari
Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Qian Liu
Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Joseph Johnson
Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Paul Stewart
Biostatistics and Bioinformatics Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Viktoriya Marusyk
Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Bin Fang
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Victoria Izumi
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Kiah Bowers
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Kelly M. Guzman
Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
John M. Koomen
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Andriy Marusyk
Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Eric K. Lau
Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Corresponding author
Summary: Brain metastasis cancer-associated fibroblasts (bmCAFs) are emerging as crucial players in the development of breast cancer brain metastasis (BCBM), but our understanding of the underlying molecular mechanisms is limited. In this study, we aim to elucidate the pathological contributions of fucosylation (the post-translational modification of proteins by the dietary sugar L-fucose) to tumor-stromal interactions that drive the development of BCBM. Here, we report that patient-derived bmCAFs secrete high levels of polio virus receptor (PVR), which enhance the invasive capacity of BC cells. Mechanistically, we find that HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR, triggering its secretion from bmCAFs. Global phosphoproteomic analysis of BC cells followed by functional verification identifies cell-cell junction and actin cytoskeletal signaling as modulated by bmCAF-secreted, -fucosylated PVR. Our findings delineate a hypoxia- and fucosylation-regulated mechanism by which bmCAFs contribute to the invasiveness of BCBM in the brain.
