Multi-Omic Characterization of Single Cells and Cell-Free Components Detected in the Cerebrospinal Fluid of Patients with Leptomeningeal Disease

Stephanie N Shishido; Amelia Marvit; Doanna Pham; Theresa Luo; Liya Xu; Jeremy Mason; Saul J Priceman; Jana Portnow; Peter Kuhn

doi:10.3390/cancers16223746

Multi-Omic Characterization of Single Cells and Cell-Free Components Detected in the Cerebrospinal Fluid of Patients with Leptomeningeal Disease

Cancers (Basel). 2024 Nov 6;16(22):3746. doi: 10.3390/cancers16223746.

Authors

Stephanie N Shishido¹, Amelia Marvit¹, Doanna Pham¹, Theresa Luo¹, Liya Xu^{2

3}, Jeremy Mason^{1

4}, Saul J Priceman^{5

6}, Jana Portnow⁷, Peter Kuhn^{1

4

8

9

10

11}

Affiliations

¹ Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA 90089, USA.
² The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
³ USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
⁶ Department of Medicine, KSOM/NCCC Center for Cancer Cellular Immunotherapy, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
⁷ Department of Medical Oncology & Therapeutics Research, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
⁸ Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
¹⁰ Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
¹¹ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

Background/objectives: Up to 30% of patients with breast cancers will develop brain or leptomeningeal metastases, and this risk is especially high with HER2-positive cancers. For patients with central nervous system metastases, cerebrospinal fluid (CSF) liquid biopsies are a promising opportunity to monitor disease, inform treatment, and predict prognosis. This pilot study investigated CSF liquid biopsy analytes from three patients diagnosed with central nervous system metastases based on imaging but not confirmed via clinical cytology.

Methods: The detection of cellular analytes with the non-enrichment high-definition single-cell assay (HDSCA3.0) workflow was compared between the CSF and matched peripheral blood (PB) samples.

Results: Circulating tumor cells (CTCs) were detected in the CSF but not the PB and were subsequently molecularly characterized using single-cell genomics and targeted multiplexed proteomics to reveal a clonal population of phenotypically heterogeneous cells. There was a lack of concordance in the copy number alteration profiles between CTCs and cell-free DNA (cfDNA) in the CSF. Extracellular vesicle surface marker analysis in CSF revealed a prominent signal among tetraspanins (CD9/CD63/CD81), with CD81 exhibiting the highest signal across all patients.

Conclusions: The data presented suggest that CSF could be a useful tool for diagnosing and assessing disease severity.

Keywords: brain metastasis; cerebrospinal fluid; circulating tumor cells; leptomeningeal disease; liquid biopsy.

Grants and funding

CIRM CLIN2-11574/California Institute for Regenerative Medicine