HIF1A signaling selectively supports proliferation of breast cancer in the brain

• Published in: Nature communications Vol. 11; no. 1; p. 6311
• Main Authors: Ebright, Richard Y., Zachariah, Marcus A., Micalizzi, Douglas S., Wittner, Ben S., Niederhoffer, Kira L., Nieman, Linda T., Chirn, Brian, Wiley, Devon F., Wesley, Benjamin, Shaw, Brian, Nieblas-Bedolla, Edwin, Atlas, Lian, Szabolcs, Annamaria, Iafrate, Anthony J., Toner, Mehmet, Ting, David T., Brastianos, Priscilla K., Haber, Daniel A., Maheswaran, Shyamala
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/51; 13/89; 45/23; 45/91; 59/5; 631/67/1347; 631/67/322; 631/67/327; 631/67/69; 64/60; Animals; Blood; Blood circulation; Brain; Brain - pathology; Brain cancer; Brain Neoplasms - blood; Brain Neoplasms - mortality; Brain Neoplasms - secondary; Brain tumors; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Hypoxia; Cell Proliferation; Female; Frontal lobe; Gene Expression Regulation, Neoplastic; Glycolysis; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mammary gland; Mammary Glands, Animal - pathology; Metabolomics; Metastases; Metastasis; Mice; multidisciplinary; Neoplastic Cells, Circulating - metabolism; RNA, Small Interfering - metabolism; RNA-Seq; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Spheroids, Cellular; Stereotaxic Techniques; Tumor cells; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20144-w

Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications. The mechanisms underlying the growth of breast cancer metastasis in the brain are unclear. Here, the authors use an intracranial injection mouse model and single-cell analysis of patient circulating tumour cells to demonstrate that increased hypoxic and HIF1A signalling promotes tumour growth in the brain.