Autocrine GMCSF Signaling Contributes to Growth of HER2 + Breast Leptomeningeal Carcinomatosis

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 18; pp. 4723 - 4735
• Main Authors: Ansari, Khairul I, Bhan, Arunoday, Saotome, Mika, Tyagi, Antariksh, De Kumar, Bony, Chen, Clara, Takaku, Motoki, Jandial, Rahul
• Format: Journal Article
• Language: English
• Published: United States 15-09-2021
• Subjects: Animals; Autocrine Communication; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - genetics; Cell Survival; Disease Models, Animal; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Meningeal Carcinomatosis - diagnosis; Meningeal Carcinomatosis - secondary; Mice; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Protein Kinase Inhibitors - pharmacology; Receptor, ErbB-2 - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-21-0259

Leptomeningeal carcinomatosis (LC) occurs when tumor cells spread to the cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord. LC is an ominous complication of cancer with a dire prognosis. Although any malignancy can spread to the leptomeninges, breast cancer, particularly the HER2
subtype, is its most common origin. HER2
breast LC (HER2
LC) remains incurable, with few treatment options, and the molecular mechanisms underlying proliferation of HER2
breast cancer cells in the acellular, protein, and cytokine-poor leptomeningeal environment remain elusive. Therefore, we sought to characterize signaling pathways that drive HER2
LC development as well as those that restrict its growth to leptomeninges. Primary HER2
LC patient-derived ("Lepto") cell lines in coculture with various central nervous system (CNS) cell types revealed that oligodendrocyte progenitor cells (OPC), the largest population of dividing cells in the CNS, inhibited HER2
LC growth
and
, thereby limiting the spread of HER2
LC beyond the leptomeninges. Cytokine array-based analyses identified Lepto cell-secreted GMCSF as an oncogenic autocrine driver of HER2
LC growth. LC/MS-MS-based analyses revealed that the OPC-derived protein TPP1 proteolytically degrades GMCSF, decreasing GMCSF signaling and leading to suppression of HER2
LC growth and limiting its spread. Finally, intrathecal delivery of neutralizing anti-GMCSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) synergistically inhibited GMCSF and suppressed activity of GMCSF effectors, reducing HER2
LC growth
. Thus, OPC suppress GMCSF-driven growth of HER2
LC in the leptomeningeal environment, providing a potential targetable axis. SIGNIFICANCE: This study characterizes molecular mechanisms that drive HER2
leptomeningeal carcinomatosis and demonstrates the efficacy of anti-GMCSF antibodies and pan-Aurora kinase inhibitors against this disease.