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

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

Journal Article · 12 February 2025 · Cancer Research Communications

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

^[1];

^[2];

^[3];

^[2];

^[3];

^[2]

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)

Cite

Export

Save

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

References (65)

The identification of a TNBC liver metastasis gene signature by sequential CTC‐xenograft modeling Vishnoi, Monika; Liu, Nikki Haowen; Yin, Wei Molecular Oncology, Vol. 13, Issue 9 https://doi.org/10.1002/1878-0261.12533	journal	July 2019
Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma Schouten, Leo J.; Rutten, Joost; Huveneers, Hans A. M. Cancer, Vol. 94, Issue 10 https://doi.org/10.1002/cncr.10541	journal	May 2002
Prognostic factors for survival in melanoma patients with brain metastases Davies, Michael A.; Liu, Ping; McIntyre, Susan Cancer, Vol. 117, Issue 8 https://doi.org/10.1002/cncr.25634	journal	October 2010
Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies Bander, Evan D.; Yuan, Melissa; Carnevale, Joseph A. Cancer, Vol. 127, Issue 12 https://doi.org/10.1002/cncr.33459	journal	March 2021
High‐speed multislice T₁ mapping using inversion‐recovery echo‐planar imaging Ordidge, R. J.; Gibbs, P.; Chapman, B. Magnetic Resonance in Medicine, Vol. 16, Issue 2 https://doi.org/10.1002/mrm.1910160205	journal	November 1990
Application of CTC discoveries for liquid biopsy: the RPL/RPS gene signature of melanoma CTCs is linked to brain metastasis onset Bowley, Tetiana Y.; Marchetti, Dario Clinical & Experimental Metastasis, Vol. 41, Issue 4 https://doi.org/10.1007/s10585-023-10255-1	journal	January 2024
Technical choices significantly alter the adaptive immune response against immunocompetent murine gliomas in a model-dependent manner Noffsinger, Breanna; Witter, Alexandra; Sheybani, Natasha Journal of Neuro-Oncology, Vol. 154, Issue 2 https://doi.org/10.1007/s11060-021-03822-7	journal	August 2021
Bring along your friends: Homotypic and heterotypic circulating tumor cell clustering to accelerate metastasis Aceto, Nicola Biomedical Journal, Vol. 43, Issue 1 https://doi.org/10.1016/j.bj.2019.11.002	journal	February 2020
Cancer Metastasis: Building a Framework Gupta, Gaorav P.; Massagué, Joan Cell, Vol. 127, Issue 4 https://doi.org/10.1016/j.cell.2006.11.001	journal	November 2006
Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis Aceto, Nicola; Bardia, Aditya; Miyamoto, David T. Cell, Vol. 158, Issue 5 https://doi.org/10.1016/j.cell.2014.07.013	journal	August 2014
Emerging Biological Principles of Metastasis Lambert, Arthur W.; Pattabiraman, Diwakar R.; Weinberg, Robert A. Cell, Vol. 168, Issue 4 https://doi.org/10.1016/j.cell.2016.11.037	journal	February 2017
Integrated analysis of multimodal single-cell data Hao, Yuhan; Hao, Stephanie; Andersen-Nissen, Erica Cell, Vol. 184, Issue 13 https://doi.org/10.1016/j.cell.2021.04.048	journal	June 2021
Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients Nguyen, Bastien; Fong, Christopher; Luthra, Anisha Cell, Vol. 185, Issue 3 https://doi.org/10.1016/j.cell.2022.01.003	journal	February 2022
Dissecting the treatment-naive ecosystem of human melanoma brain metastasis Biermann, Jana; Melms, Johannes C.; Amin, Amit Dipak Cell, Vol. 185, Issue 14 https://doi.org/10.1016/j.cell.2022.06.007	journal	July 2022
SnapShot: Eukaryotic ribosome biogenesis I Hurt, Ed; Cheng, Jingdong; Baβler, Jochen Cell, Vol. 186, Issue 10 https://doi.org/10.1016/j.cell.2023.04.030	journal	May 2023
Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes Yang, Yu; Chen, Xueyan; Pan, Jieying Cell, Vol. 187, Issue 17 https://doi.org/10.1016/j.cell.2024.06.038	journal	August 2024
Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study Cimino-Mathews, Ashley; Ye, Xiaobu; Meeker, Alan Human Pathology, Vol. 44, Issue 10 https://doi.org/10.1016/j.humpath.2013.03.010	journal	October 2013
Melanoma in the liver: Oxidative stress and the mechanisms of metastatic cell survival Obrador, Elena; Salvador, Rosario; López-Blanch, Rafael Seminars in Cancer Biology, Vol. 71 https://doi.org/10.1016/j.semcancer.2020.05.001	journal	June 2021
Nonirradiated NOD,B6.SCID Il2rγ−/− KitW41/W41 (NBSGW) Mice Support Multilineage Engraftment of Human Hematopoietic Cells McIntosh, Brian E.; Brown, Matthew E.; Duffin, Bret M. Stem Cell Reports, Vol. 4, Issue 2 https://doi.org/10.1016/j.stemcr.2014.12.005	journal	February 2015
B Lymphocytes and Cancer: A Love–Hate Relationship Yuen, Grace J.; Demissie, Ezana; Pillai, Shiv Trends in Cancer, Vol. 2, Issue 12 https://doi.org/10.1016/j.trecan.2016.10.010	journal	December 2016
The pre-metastatic niche: is metastasis random? Cox, Thomas R.; Gartland, Alison; Erler, Janine T. BoneKEy Reports, Vol. 1, Issue 5 https://doi.org/10.1038/bonekey.2012.80	journal	May 2012
Challenges in circulating tumour cell research Alix-Panabières, Catherine; Pantel, Klaus Nature Reviews Cancer, Vol. 14, Issue 9 https://doi.org/10.1038/nrc3820	journal	July 2014
Targeted agents and immunotherapies: optimizing outcomes in melanoma Luke, Jason J.; Flaherty, Keith T.; Ribas, Antoni Nature Reviews Clinical Oncology, Vol. 14, Issue 8 https://doi.org/10.1038/nrclinonc.2017.43	journal	April 2017
Melanoma metastasis: new concepts and evolving paradigms Damsky, W. E.; Theodosakis, N.; Bosenberg, M. Oncogene, Vol. 33, Issue 19 https://doi.org/10.1038/onc.2013.194	journal	June 2013
Molecular characterization of breast cancer CTCs associated with brain metastasis Boral, Debasish; Vishnoi, Monika; Liu, Haowen N. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00196-1	journal	August 2017
Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma Werner-Klein, Melanie; Scheitler, Sebastian; Hoffmann, Martin Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-017-02674-y	journal	February 2018
A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies Song, Yuanbin; Rongvaux, Anthony; Taylor, Ashley Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-018-08166-x	journal	January 2019
Liquid biopsy enters the clinic — implementation issues and future challenges Ignatiadis, Michail; Sledge, George W.; Jeffrey, Stefanie S. Nature Reviews Clinical Oncology, Vol. 18, Issue 5 https://doi.org/10.1038/s41571-020-00457-x	journal	January 2021
Neutrophils escort circulating tumour cells to enable cell cycle progression Szczerba, Barbara Maria; Castro-Giner, Francesc; Vetter, Marcus Nature, Vol. 566, Issue 7745 https://doi.org/10.1038/s41586-019-0915-y	journal	February 2019
IgA transcytosis and antigen recognition govern ovarian cancer immunity Biswas, Subir; Mandal, Gunjan; Payne, Kyle K. Nature, Vol. 591, Issue 7850 https://doi.org/10.1038/s41586-020-03144-0	journal	February 2021
Structural mechanism of angiogenin activation by the ribosome Loveland, Anna B.; Koh, Cha San; Ganesan, Robin Nature, Vol. 630, Issue 8017 https://doi.org/10.1038/s41586-024-07508-8	journal	May 2024
Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression Cao, Shaolong; Wang, Jennifer R.; Ji, Shuangxi Nature Biotechnology, Vol. 40, Issue 11 https://doi.org/10.1038/s41587-022-01342-x	journal	June 2022
Dictionary learning for integrative, multimodal and scalable single-cell analysis Hao, Yuhan; Stuart, Tim; Kowalski, Madeline H. Nature Biotechnology, Vol. 42, Issue 2 https://doi.org/10.1038/s41587-023-01767-y	journal	May 2023
Ribosome heterogeneity in stem cells and development Li, Dan; Wang, Jianlong Journal of Cell Biology, Vol. 219, Issue 6 https://doi.org/10.1083/jcb.202001108	journal	April 2020
Reactome: a database of reactions, pathways and biological processes Croft, D.; O'Kelly, G.; Wu, G. Nucleic Acids Research, Vol. 39, Issue Database https://doi.org/10.1093/nar/gkq1018	journal	November 2010
Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities Eroglu, Zeynep; Holmen, Sheri L.; Chen, Qing Pigment Cell & Melanoma Research, Vol. 32, Issue 3 https://doi.org/10.1111/pcmr.12771	journal	February 2019
Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities Karz, Alcida; Dimitrova, Maya; Kleffman, Kevin Pigment Cell & Melanoma Research, Vol. 35, Issue 6 https://doi.org/10.1111/pcmr.13059	journal	September 2022
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis Ebright, Richard Y.; Lee, Sooncheol; Wittner, Ben S. Science, Vol. 367, Issue 6485 https://doi.org/10.1126/science.aay0939	journal	March 2020
A blueprint for tumor-infiltrating B cells across human cancers Ma, Jiaqiang; Wu, Yingcheng; Ma, Lifeng Science, Vol. 384, Issue 6695 https://doi.org/10.1126/science.adj4857	journal	May 2024
Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers Berghoff, Anna S.; Schur, Sophie; Füreder, Lisa M. ESMO Open, Vol. 1, Issue 2 https://doi.org/10.1136/esmoopen-2015-000024	journal	January 2016
AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective Talmadge, J. E.; Fidler, I. J. Cancer Research, Vol. 70, Issue 14 https://doi.org/10.1158/0008-5472.CAN-10-1040	journal	July 2010
Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow–Resident Melanoma CTCs Vishnoi, Monika; Boral, Debasish; Liu, Haowen Cancer Research, Vol. 78, Issue 18 https://doi.org/10.1158/0008-5472.CAN-18-0644	journal	September 2018
Translational Regulation of Cancer Metastasis Micalizzi, Douglas S.; Ebright, Richard Y.; Haber, Daniel A. Cancer Research, Vol. 81, Issue 3 https://doi.org/10.1158/0008-5472.CAN-20-2720	journal	February 2021
Ribosome Biogenesis: A Central Player in Cancer Metastasis and Therapeutic Resistance Elhamamsy, Amr R.; Metge, Brandon J.; Alsheikh, Heba A. Cancer Research, Vol. 82, Issue 13 https://doi.org/10.1158/0008-5472.CAN-21-4087	journal	March 2022
The Evolving Landscape of B Cells in Cancer Metastasis Ramos, Monika J.; Lui, Asona J.; Hollern, Daniel P. Cancer Research, Vol. 83, Issue 23 https://doi.org/10.1158/0008-5472.CAN-23-0620	journal	October 2023
Circulating Tumor Cells and Early Relapse in Node-positive Melanoma Lucci, Anthony; Hall, Carolyn S.; Patel, Sapna P. Clinical Cancer Research, Vol. 26, Issue 8 https://doi.org/10.1158/1078-0432.CCR-19-2670	journal	April 2020
Metastasis-Initiating Cells and Ecosystems Massagué, Joan; Ganesh, Karuna Cancer Discovery, Vol. 11, Issue 4 https://doi.org/10.1158/2159-8290.CD-21-0010	journal	April 2021
Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity Steinkamp, Mara P.; Lagutina, Irina; Brayer, Kathryn J. Cancer Research Communications, Vol. 3, Issue 2 https://doi.org/10.1158/2767-9764.CRC-22-0300	journal	February 2023
The RPL/RPS Gene Signature of Melanoma CTCs Associates with Brain Metastasis Bowley, Tetiana Y.; Lagutina, Irina V.; Francis, Carol Cancer Research Communications, Vol. 2, Issue 11 https://doi.org/10.1158/2767-9764.CRC-22-0337	journal	November 2022
From mice to humans: developments in cancer immunoediting Teng, Michele W. L.; Galon, Jerome; Fridman, Wolf-Herman Journal of Clinical Investigation, Vol. 125, Issue 9 https://doi.org/10.1172/JCI80004	journal	August 2015
Deep neural network based tissue deconvolution of circulating tumor cell RNA Yan, Fengyao; Jiang, Limin; Ye, Fei Journal of Translational Medicine, Vol. 21, Issue 1 https://doi.org/10.1186/s12967-023-04663-w	journal	November 2023
Patterns of ribosomal protein expression specify normal and malignant human cells Guimaraes, Joao C.; Zavolan, Mihaela Genome Biology, Vol. 17, Issue 1 https://doi.org/10.1186/s13059-016-1104-z	journal	November 2016
Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient Sperduto, Paul W.; Mesko, Shane; Li, Jing Journal of Clinical Oncology, Vol. 38, Issue 32 https://doi.org/10.1200/JCO.20.01255	journal	November 2020
Biology, detection, and clinical implications of circulating tumor cells Joosse, Simon A.; Gorges, Tobias M.; Pantel, Klaus EMBO Molecular Medicine, Vol. 7, Issue 1 https://doi.org/10.15252/emmm.201303698	journal	November 2014
On the Origin of Cancer Metastasis Seyfried, Thomas N.; Huysentruyt, Leanne C. Critical Reviews in Oncogenesis, Vol. 18, Issue 1 - 2 https://doi.org/10.1615/CritRevOncog.v18.i1-2.40	journal	January 2013
Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases In, Gino K.; Poorman, Kelsey; Saul, Michelle Oncotarget, Vol. 11, Issue 33 https://doi.org/10.18632/oncotarget.27686	journal	August 2020
Tumor microenvironment B cells increase bladder cancer metastasisviamodulation of the IL-8/androgen receptor (AR)/MMPs signals Ou, Zhenyu; Wang, Yongjie; Liu, Longfei Oncotarget, Vol. 6, Issue 28 https://doi.org/10.18632/oncotarget.4569	journal	July 2015
Survival after surgical treatment of brain metastases from lung cancer: a follow-up study of 231 patients treated between 1976 and 1991 Wroński, Marek; Arbit, Ehud; Burt, Michael Journal of Neurosurgery, Vol. 83, Issue 4 https://doi.org/10.3171/jns.1995.83.4.0605	journal	October 1995
B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies Willsmore, Zena N.; Harris, Robert J.; Crescioli, Silvia Frontiers in Immunology, Vol. 11 https://doi.org/10.3389/fimmu.2020.622442	journal	January 2021
Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers Zhong, Ziwen; Nan, Ke; Weng, Meilin Frontiers in Immunology, Vol. 12 https://doi.org/10.3389/fimmu.2021.765044	journal	November 2021
The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance Dianat-Moghadam, Hassan; Azizi, Mehdi; Eslami-S, Zahra Cancers, Vol. 12, Issue 4 https://doi.org/10.3390/cancers12040867	journal	April 2020
Heterogeneity of Circulating Tumor Cell Neoplastic Subpopulations Outlined by Single-Cell Transcriptomics Pauken, Christine M.; Kenney, Shelby Ray; Brayer, Kathryn J. Cancers, Vol. 13, Issue 19 https://doi.org/10.3390/cancers13194885	journal	September 2021
Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis Bowley, Tetiana Y.; Merkley, Seth D.; Lagutina, Irina V. Cancers, Vol. 15, Issue 21 https://doi.org/10.3390/cancers15215263	journal	November 2023
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling Sprouse, Marc L.; Welte, Thomas; Boral, Debasish International Journal of Molecular Sciences, Vol. 20, Issue 8 https://doi.org/10.3390/ijms20081916	journal	April 2019
The immune landscape of human tumors Bindea, Gabriela; Mlecnik, Bernhard; Angell, Helen K. OncoImmunology, Vol. 3, Issue 2 https://doi.org/10.4161/onci.27456	journal	January 2014

Similar Records

ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

Journal Article · 2010 · Biochemical and Biophysical Research Communications · OSTI ID:22202817

Ungerer, Christopher; Doberstein, Kai; Buerger, Claudia; +7 more

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

Journal Article · 2016 · Biochemical and Biophysical Research Communications · OSTI ID:22696583

Hong, Seok-Ho; Shin, Minsang; Heo, Hye-Ryeon

Increased iofetamine I 123 brain uptake in metastatic melanoma

Journal Article · 1988 · Arch. Neurol.; (United States) · OSTI ID:6601470

Nagel, J S; Ichise, M; Mueller, S P; +5 more

Related Subjects

60 APPLIED LIFE SCIENCES

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

Citation Formats

References (65)

Similar Records

Related Subjects