A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain–Liver Metastasis Axis

Bowley, Tetiana Yuriyivna; Ortiz, Mireya C.; Lagutina, Irina V.; Steinkamp, Mara P.; Fahy, Bridget N.; Tawfik, Bernard; Harari-Turquie, Moises; Marchetti, Dario

doi:10.1158/2767-9764.crc-24-0498

A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain–Liver Metastasis Axis

Journal Article · Wed Feb 12 00:00:00 EST 2025 · Cancer Research Communications

DOI:https://doi.org/10.1158/2767-9764.crc-24-0498· OSTI ID:2538420

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Univ. of New Mexico, Albuquerque, NM (United States). Health Sciences Center; Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Univ. of New Mexico, Albuquerque, NM (United States). Health Sciences Center
Univ. of New Mexico, Albuquerque, NM (United States). Comprehensive Cancer Center

Melanoma brain metastasis is linked to dismal prognosis and low overall survival and is detected in up to 80% of patients at autopsy. Circulating tumor cells (CTC) are the smallest functional units of cancer and precursors of fatal metastasis. We previously used an unbiased multilevel approach to discover a unique ribosomal protein large/small subunit (RPL/RPS) CTC gene signature associated with melanoma brain metastasis. In this study, we hypothesized that CTC-driven melanoma brain metastasis secondary metastasis (“metastasis of metastasis” per clinical scenarios) has targeted organ specificity for the liver. We injected parallel cohorts of immunodeficient and newly developed humanized NBSGW (huNBSGW) mice with cells from CTC-derived melanoma brain metastasis to identify secondary metastatic patterns. We found the presence of a melanoma brain–liver metastasis axis in huNBSGW mice. Furthermore, RNA sequencing analysis of tissues showed a significant upregulation of the RPL/RPS CTC gene signature linked to metastatic spread to the liver. Additional RNA sequencing of CTCs from huNBSGW blood revealed extensive CTC clustering with human B cells in these mice. CTC:B-cell clusters were also upregulated in the blood of patients with primary melanoma and maintained either in CTC-driven melanoma brain metastasis or melanoma brain metastasis CTC–derived cells promoting liver metastasis. CTC-generated tumor tissues were interrogated at single-cell gene and protein expression levels (10x Genomics Xenium and HALO spatial biology platforms, respectively). Collectively, our findings suggest that heterotypic CTC:B-cell interactions can be critical at multiple stages of metastasis.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2538420

Report Number(s):: LA-UR--24-29474

Journal Information:: Cancer Research Communications, Journal Name: Cancer Research Communications Journal Issue: 2 Vol. 5; ISSN 2767-9764

Publisher:: American Association for Cancer ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain–Liver Metastasis Axis

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