Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation

Juma R R Ward; Paul B Martin

doi:10.1242/jcs.261225

Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation

Juma R R Ward, Paul B Martin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

3 Citations (Scopus)

Abstract

Previous clinical studies and work in mouse models have indicated that platelets and microclots may function as enablers in the recruitment of immune cells to the pre-metastatic cancer niche leading to efficacious extravasation of cancer cells through the vessel wall. Here we investigate the interaction between platelets, endothelial cells, inflammatory cells and engrafted human and zebrafish cancer cells by live imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging of each lineage reveals their dynamic behaviour and potential roles in these events, and we test function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrin, and warfarin treatment to inhibit clotting, both abrogate extravasation of cancer cells. Inflammatory phenotype appears fundamental, and we show that forcing a pro-inflammatory, TNFa+ve phenotype is inhibitory to extravasation of cancer cells.

Original language	English
Article number	jcs261225
Journal	Journal of Cell Science
Volume	136
Issue number	18
DOIs	https://doi.org/10.1242/jcs.261225
Publication status	Published - 28 Sept 2023

Bibliographical note

Funding Information:
We thank all members in the Martin lab for guidance and advice during the drafting of this manuscript. We also thank the zebrafish research community for generation and supply of fish lines, Lorna Hodgson for her assistance with electron microscopy, the Wolfson Bioimaging Facility for use of their equipment, and Richard White and Jacky Goetz for the ZMEL cancer cell line. J.W. was supported by a Wellcome Trust PhD studentship from the University of Bristol ‘Molecular Cell Dynamics’ PhD programme, and work in P.M.’s lab was funded by a Cancer Research UK programme grant and an Investigator Award from the Wellcome Trust. Open Access funding provided by University of Bristol. Deposited in PMC for immediate release.

Funding Information:
J.W. was supported by a Wellcome Trust PhD studentship from the University of Bristol ‘Molecular Cell Dynamics’ PhD programme, and work in P.M.’s lab was funded by a Cancer Research UK programme grant and an Investigator Award from the Wellcome Trust. Open Access funding provided by University of Bristol. Deposited in PMC for immediate release.

Publisher Copyright:
© 2023. Published by The Company of Biologists Ltd.

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title = "Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation",

abstract = "Previous clinical studies and work in mouse models have indicated that platelets and microclots may function as enablers in the recruitment of immune cells to the pre-metastatic cancer niche leading to efficacious extravasation of cancer cells through the vessel wall. Here we investigate the interaction between platelets, endothelial cells, inflammatory cells and engrafted human and zebrafish cancer cells by live imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging of each lineage reveals their dynamic behaviour and potential roles in these events, and we test function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrin, and warfarin treatment to inhibit clotting, both abrogate extravasation of cancer cells. Inflammatory phenotype appears fundamental, and we show that forcing a pro-inflammatory, TNFa+ve phenotype is inhibitory to extravasation of cancer cells.",

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note = "Funding Information: We thank all members in the Martin lab for guidance and advice during the drafting of this manuscript. We also thank the zebrafish research community for generation and supply of fish lines, Lorna Hodgson for her assistance with electron microscopy, the Wolfson Bioimaging Facility for use of their equipment, and Richard White and Jacky Goetz for the ZMEL cancer cell line. J.W. was supported by a Wellcome Trust PhD studentship from the University of Bristol {\textquoteleft}Molecular Cell Dynamics{\textquoteright} PhD programme, and work in P.M.{\textquoteright}s lab was funded by a Cancer Research UK programme grant and an Investigator Award from the Wellcome Trust. Open Access funding provided by University of Bristol. Deposited in PMC for immediate release. Funding Information: J.W. was supported by a Wellcome Trust PhD studentship from the University of Bristol {\textquoteleft}Molecular Cell Dynamics{\textquoteright} PhD programme, and work in P.M.{\textquoteright}s lab was funded by a Cancer Research UK programme grant and an Investigator Award from the Wellcome Trust. Open Access funding provided by University of Bristol. Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2023. Published by The Company of Biologists Ltd.",

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N2 - Previous clinical studies and work in mouse models have indicated that platelets and microclots may function as enablers in the recruitment of immune cells to the pre-metastatic cancer niche leading to efficacious extravasation of cancer cells through the vessel wall. Here we investigate the interaction between platelets, endothelial cells, inflammatory cells and engrafted human and zebrafish cancer cells by live imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging of each lineage reveals their dynamic behaviour and potential roles in these events, and we test function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrin, and warfarin treatment to inhibit clotting, both abrogate extravasation of cancer cells. Inflammatory phenotype appears fundamental, and we show that forcing a pro-inflammatory, TNFa+ve phenotype is inhibitory to extravasation of cancer cells.

AB - Previous clinical studies and work in mouse models have indicated that platelets and microclots may function as enablers in the recruitment of immune cells to the pre-metastatic cancer niche leading to efficacious extravasation of cancer cells through the vessel wall. Here we investigate the interaction between platelets, endothelial cells, inflammatory cells and engrafted human and zebrafish cancer cells by live imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging of each lineage reveals their dynamic behaviour and potential roles in these events, and we test function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrin, and warfarin treatment to inhibit clotting, both abrogate extravasation of cancer cells. Inflammatory phenotype appears fundamental, and we show that forcing a pro-inflammatory, TNFa+ve phenotype is inhibitory to extravasation of cancer cells.

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DO - 10.1242/jcs.261225

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Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation

Abstract

Bibliographical note

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