Tubulin-Based Microtentacles Aid in Heterotypic Clustering of Neutrophil-Differentiated HL-60 Cells and Breast Tumor Cells

Julia A Ju; Keyata N Thompson; David A Annis; Makenzy L Mull; Darin E Gilchrist; Aidan Moriarty; Katarina T Chang; Megan B Stemberger; Michael J Noto; Michele I Vitolo; Stuart S Martin

doi:10.1002/advs.202409260

Tubulin-Based Microtentacles Aid in Heterotypic Clustering of Neutrophil-Differentiated HL-60 Cells and Breast Tumor Cells

Adv Sci (Weinh). 2024 Dec 18:e2409260. doi: 10.1002/advs.202409260. Online ahead of print.

Authors

Julia A Ju^{1

2}, Keyata N Thompson¹, David A Annis^{1

3}, Makenzy L Mull^{1

2}, Darin E Gilchrist^{1

2}, Aidan Moriarty^{1

2}, Katarina T Chang^{1

2}, Megan B Stemberger¹, Michael J Noto⁴, Michele I Vitolo^{1

2

5}, Stuart S Martin^{1

2

5

6}

Affiliations

¹ Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
² Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD, 21201, USA.
³ Graduate Program in Epidemiology and Human Genetics, University of Maryland Baltimore, 800 W. Baltimore St., Baltimore, MD, 21201, USA.
⁴ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD, 21201, USA.
⁵ Department of Pharmacology and Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
⁶ United States Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, 21201, USA.

PMID: 39696759
DOI: 10.1002/advs.202409260

Abstract

Circulating tumor cells (CTCs) travel through the vasculature to seed secondary sites and serve as direct precursors of metastatic outgrowth for many solid tumors. Heterotypic cell clusters form between CTCs and white blood cells (WBCs) and recent studies report that a majority of these WBCs are neutrophils in patient and mouse models. The lab discovered that CTCs produce tubulin-based protrusions, microtentacles (McTNs), which promote reattachment, retention in distant sites during metastasis and formation of tumor cell clusters. Neutrophil-CTC clusters help CTCs survive the harsh vascular environment to promote successful metastasis, however, the specific mechanism of this interaction is not fully understood. Utilizing TetherChip technology, it is found that primary and differentiated neutrophils produce McTNs composed of detyrosinated and acetylated α-tubulin and vimentin. Neutrophil McTNs aid in cluster formation, migration, and reattachment, which are suppressed with the tubulin-depolymerizing agent, Vinorelbine. Co-culturing differentiated neutrophils and tumor cells formed heterotypic clusters that enhanced migration. CTC-neutrophil clusters have higher metastatic efficiency, and by demonstrating that neutrophils form McTNs, a new possible mechanism for how neutrophils interact with tumor cells is revealed. These findings further support the idea that developing cluster-disrupting therapies can provide a new targeted strategy to reduce the metastatic potential of cancer cells.

Keywords: HL‐60 cells; TetherChip; circulating tumor cells; heterotypic cluster; metastasis; microtentacles; neutrophils.

Abstract

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