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Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy

Oncogene volume 41, pages 1337–1351 (2022)Cite this article

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Abstract

Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients’ demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1), and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients’ tumors. These rare CX3CR1High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1Low) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as a novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation.

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Fig. 1: CX3CR1High cancer cells are detected in patient samples from primary and metastatic breast and prostate cancers.
Fig. 2: Formation of tumor spheroids depends on CX3CR1 expression and signaling.
Fig. 3: Sub-populations of CX3CR1High cancer cells demonstrate stemness features.
Fig. 4: CX3CR1 promotes colonization of disseminated tumor cells. Human cancer cells co-expressing GFP and Luc2 luciferase were grafted in the systemic blood circulation of mice, which were either killed 24 h later to assess tumor seeding or longitudinally monitored for tumor growth by bioluminescence imaging.
Fig. 5: CX3CR1High cells are tumor-initiating.
Fig. 6: CX3CR1Low cells exhibit phenotypic plasticity.
Fig. 7: CX3CR1High cells show resistance to docetaxel.

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Data availability

RNA-Seq data have been deposited in the NCBI GEO with the submission code PRJNA736860.

Molecular Signature database (MSigDB) and gene set enrichment analysis were utilized for pathways analyses.

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Acknowledgements

This work was supported by NCI grant R01-CA202929 (AF and OM), DoD grant BC150659 (AF), Wallace H. Coulter Foundation (AF and OM), Pennsylvania Breast Cancer Coalition (AF), Exceptional Project Grant from Breast Cancer Alliance (AF), and the Sidney Kimmel Cancer Center (SKCC) Support Grant 5P30CA056036-21 (AF). We would like to thank: Dr. Meenhard Herlyn (Wistar Institute, Philadelphia, PA) and Dr. Edward Hartsough (Pharmacology and Physiology, Drexel University College of Medicine) for providing the WM793 and 1205Lu human melanoma cell lines; Dr. Edward Hartsough (Pharmacology and Physiology, Drexel University College of Medicine) and Dr. Josep Domingo-Domenech (Cancer Biology, SKCC at Thomas Jefferson University) for helpful discussions; Dr. Paolo Fortina, Professor of Cancer Biology and Director of the Cancer Genomics and Translational Research/Pathology core services at SKCC for consultation and advice with RNA Sequencing; Ms. Shannon Cremin (Translational Research Project Manager), Ms. Danielle Wentworth (Biorepository Manager) and the SKCC Biorepository of Thomas Jefferson University for providing the human specimens used in this study. The authors are also grateful to Dr. Bradley Nash (Director, Office of Scientific Communications, Department of Pharmacology and Physiology, Drexel University College of Medicine) for critically reading and editing the manuscript.

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Author notes

  1. Ramanpreet Kaur

    Present address: Champions Oncology, 1330 Piccard Drive, Rockville, MD, 20850, USA

  2. Chen Qian

    Present address: Samuel Oschin Cancer Center, Cedars-Sinai, Los Angeles, CA, 90048, USA

  3. Maria Castelli

    Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

  4. These authors contributed equally: Ramanpreet Kaur and Chen Qian.

Authors and Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    Anthony DiNatale, Ramanpreet Kaur, Chen Qian, Jieyi Zhang, Michael Marchioli, Darin Ipe, Maria Castelli, Olimpia Meucci & Alessandro Fatatis

  2. Department of Cancer Biology, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Chris M. McNair & Gaurav Kumar

  3. Cancer Informatics, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Chris M. McNair

  4. Program in Immune Cell Regulation & Targeting, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Olimpia Meucci

  5. Program in Translational and Cellular Oncology at Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Alessandro Fatatis

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  1. Anthony DiNatale
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Contributions

AD: Conceptualization, investigation, data generation (molecular biology, biochemistry, flow cytometry and cell sorting, cell culturing and in vitro treatments), data analysis, methodology, manuscript writing, reviewing and editing. RK: Conceptualization, data generation (tumor spheroids assay, biochemistry, chemotaxis assay, animal models of tumor seeding and initiation, flow cytometry and cell sorting), data analysis, manuscript editing. CQ: Conceptualization, data generation (tumor spheroids assay, flow cytometry and cell sorting, animal models of tumor seeding). JZ: Data generation (biochemistry, flow cytometry and cell sorting), data analysis (human samples), manuscript editing. MM: Data generation (immunohistochemistry). DI: Data generation (Flow cytometry and sorting), data analysis (human samples), methodology, manuscript editing. MC: Data generation (immunohistochemistry, biochemistry). CMM: Data analysis (RNA sequencing) and data curation. GK: Data generation and analysis (RNA sequencing), data curation, manuscript reviewing and editing. OM: Conceptualization, resources, formal analysis, funding acquisition. AF: Conceptualization, investigation, supervision, resources, funding acquisition, data analysis, formal analysis, methodology, writing original draft, manuscript reviewing and editing.

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Correspondence to Alessandro Fatatis.

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DiNatale, A., Kaur, R., Qian, C. et al. Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy. Oncogene 41, 1337–1351 (2022). https://doi.org/10.1038/s41388-021-02174-w

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  • DOI: https://doi.org/10.1038/s41388-021-02174-w

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