
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.003
vdae090.003
Final Category: Basic Science Brain Metastases
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSBM-03 TARGETABLE GENE EXPRESSION CHANGES MEDIATE EXTRAVASATION OF BREAST CANCER CELLS FROM THE CIRCULATION AND LOCAL PROLIFERATION IN THE BRAIN
Kalistratova Venina UCSF, San Francisco, CA, USA

Morshed Ramin UCSF Department of Neurological Surgery, San Francisco, CA, USA

Chalif Eric UCSF, San Francisco, CA, USA

Gill Sabraj UCSF, San Francisco, CA, USA

Khela Harmon UCSF, San Francisco, CA, USA

Lad Meeki UCSF, San Francisco, CA, USA

Sati Ankita UCSF, San Francisco, CA, USA

Mathur Aakriti UCSF, San Francisco, CA, USA

Aghi Manish UCSF Department of Neurological Surgery, San Francisco, CA, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i1i1
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

As breast cancer migrates into the brain, it acquires distinct genomic, immunologic and phenotypic changes through interactions with the local microenvironment. We sought to determine how targetable gene expression changes mediate breast cancer extravasation into and proliferation within the brain. We created a brain metastatic cell line (“brain-seeking”) via serial intracardiac injection of mCherry+ 4T1 breast cancer cells in Balb/c mice and flow cytometry isolation of micrometastases. We conducted in vitro and in-vivo studies to uncover immunological and genetic differences between primary breast cancer and brain metastases. In culture, we observed significant upregulation in adhesion (p=0.01) and invasion (p=0.0004) along with upregulation of adhesion-promoting genes such as Sdc3, Serpine2 or ECM1 in the brain-seeking cells. We observed significant differences in survival of Balb/c mice injected intracranially with brain-seeking cells compared to the 4T1 breast cancer cells (p=0.04). In the mammary fat pad (MFP), parental 4T1 cells caused increased mortality compared to brain-seeking cells (p=0.003). This rejection of brain-seeking 4T1 cells in the MFP could be due to their prior adaptation to the brain microenvironment, while rejection of parental 4T1 cells in the brain microenvironment could be due to them lacking those adaptations. Consistent with this finding, of 20,382 analyzed genes in both cell lines, 108 related to immune regulation were significantly upregulated in brain-seeking cells including Cxcl1, Dusp1, C3. Flow cytometry showed increased cytotoxic and helper T cells in intracranially injected parental 4T1 cells vs. brain-seeking cells (p <0.001). In the MFP, however, 4T1 parental cells displayed CD3+ T cell depletion and an increased number of neutrophils (p <0.05) while the “brain-seeking cells” showed increased numbers of CD3+ and CD4+ cells (p <0.01) and macrophages (p<0.05). These findings suggest that brain metastases evolve from their primary tumor through adhesive and invasive adaptations promoting extravasation, along with unique immunological adaptations that allow them to proliferate free of immune surveillance in the brain microenvironment.
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