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

Abstract

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 in vitro and in vivo, 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 in vivo. 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.

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“…This study was carried out in compliance with the ARRIVE guidelines. All NOD- scid IL2Rgamma null (NOD/SCID) mouse studies were approved by the COH Institutional Animal Care and Use Committee (protocol #10044) 98 and carried out in accordance with the relevant guidelines and regulations.…”

ICAM2 initiates trans-blood-CSF barrier migration and stemness properties in leptomeningeal metastasis of triple-negative breast cancer

“…In parenchymal metastasis, tumor cells enter the parenchyma through the endothelium surrounding the vasculature and the connected astrocytes, thereby causing perivascular proliferation [ 20 – 22 ]. In LM, tumor cells enter the CSF compartment and adhere to the pia mater surrounding the brain and spinal cord [ 2 , 8 , 23 – 25 ]. As revealed by histopathological analysis, our xenograft model demonstrated two major subtypes of CNS-metastatic cells: (1) tumor cells adhered to the blood–brain barrier and (2) tumor cells colonized the pia mater in the entire brain section (Supplementary Fig.…”

“…LM is diagnosed among 1–15% of patients with systemic malignancies such as breast cancer (BC), particularly triple-negative breast cancer (TNBC) with characteristics of LM [ 1 , 3 , 4 ]. Currently, patients with LM exhibit poor clinical outcomes, including cognitive disorders and poor likelihood of survival (less than 1 year), and therapeutic strategies are limited [ 5 – 8 ]. Clinical studies have demonstrated that compared with systemic treatment alone, in a randomized phase III trial, intrathecal liposomal cytarabine combined with systemic treatment improved progression-free survival among patients with LM in BC [ 9 , 10 ].…”

Cytokine Landscape in Central Nervous System Metastases

“…Moreover, it was demonstrated by the Jandial group that the cytokine Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) plays a major role in the establishment of LM from HER2+ breast cancer. Indeed, when they inhibited GM-CSF with anti-GM-CSF antibodies combined with pan-Aurora kinase inhibitor (CCT137690), they reduced HER2+ LM cell growth in vivo [ 79 ]. Similarly, when they used the JIB04 treatment, which is a selective inhibitor of Jumonji demethylases overexpressed in their LM cell lines, they observed a downregulation of GM-CSF expression that prevents cancer cell proliferation [ 80 ].…”