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

doi:10.1016/j.celrep.2023.113463

Brain metastasis-associated fibroblasts secrete fucosylated PVR/CD155 that induces breast cancer invasion

Cell Rep. 2023 Dec 26;42(12):113463. doi: 10.1016/j.celrep.2023.113463. Epub 2023 Nov 22.

Authors

Emma Adhikari¹, Qian Liu¹, Joseph Johnson², Paul Stewart³, Viktoriya Marusyk⁴, Bin Fang⁵, Victoria Izumi⁵, Kiah Bowers⁵, Kelly M Guzman², John M Koomen⁶, Andriy Marusyk⁴, Eric K Lau⁷

Affiliations

¹ 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.
² Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
³ Biostatistics and Bioinformatics Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴ Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁵ Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ 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.
⁷ 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. Electronic address: eric.lau@moffitt.org.

PMID: 37995180
DOI: 10.1016/j.celrep.2023.113463

Abstract

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.

Keywords: CP: Cancer; brain metastasis; breast cancer; cancer-associated fibroblasts; fucosylation; hypoxia; invasion; polio virus receptor; protein secretion.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain Neoplasms* / pathology
Breast Neoplasms* / pathology
Cancer-Associated Fibroblasts* / pathology
Female
Fibroblasts / pathology
Humans
Receptors, Virus

Substances

Receptors, Virus
poliovirus receptor

Grants and funding

P30 CA076292/CA/NCI NIH HHS/United States