Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression

Opzoomer, James W.; Anstee, Joanne E.; Dean, Isaac; Hill, Emily; Bouybayoune, Ihssane; Caron, Jonathan; Muliaditan, Tamara; Gordon, Peter M.; Sosnowska, Dominika; Nuamah, Rosamond; Pinder, Sarah; Ng, Tony; Dazzi, Francesco; Kordasti, Shahram; Withers, David R.; Lawrence, Toby; Arnold, James N.

doi:10.1126/sciadv.abg9518

Cited by 49 publications

(71 citation statements)

References 86 publications

(122 reference statements)

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“…One subset of TAMs reside in close proximity to blood vasculature (<15-20 µm) (14)(15)(16) and are termed perivascular TAMs (PvTAMs). PvTAMs support a variety of pro-tumoral functions including neo-angiogenesis (15,16), metastasis (3,17,18) and facilitate tumor recurrence post chemotherapy (19). Recently, we demonstrated that a subset of PvTAMs expressing lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) form a pro-angiogenic Pv niche with a population of pericyte-like cancer associated fibroblasts (CAFs) and orchestrate the platelet-derived growth factor-C (PDGF-C)-dependent expansion of the CAF population with the growing tumor (16).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we demonstrated that a subset of PvTAMs expressing lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) form a pro-angiogenic Pv niche with a population of pericyte-like cancer associated fibroblasts (CAFs) and orchestrate the platelet-derived growth factor-C (PDGF-C)-dependent expansion of the CAF population with the growing tumor (16). Lyve-1 was traditionally considered a marker of lymphatic endothelium (20), but has emerged as selective marker for a sub-population of Pv tissue-resident macrophages (21)(22)(23)(24)(25) and TAMs (16,26). Depleting Lyve-1 + PvTAMs in the spontaneous mouse mammary tumor virus polyomavirus middle T antigen (MMTV-PyMT) murine model of breast cancer using liposome-based approaches resulted in tumor control, highlighting the importance of the TAM subset in cancer progression and formation of the Pv niche (16).…”

Section: Introductionmentioning

confidence: 99%

“…Heterogeneity within the tumor associated macrophage (TAM) population arises from their site of origin (9) and the influence of environmental cues within the tumor microenvironment (TME) (3,10,11), which can be guided by both spatial (12,13) and temporal (11) parameters. One subset of TAMs reside in close proximity to blood vasculature (<15-20 µm) (14)(15)(16) and are termed perivascular TAMs (PvTAMs). PvTAMs support a variety of pro-tumoral functions including neo-angiogenesis (15,16), metastasis (3,17,18) and facilitate tumor recurrence post chemotherapy (19).…”

Section: Introductionmentioning

confidence: 99%

“…PvTAMs support a variety of pro-tumoral functions including neo-angiogenesis (15,16), metastasis (3,17,18) and facilitate tumor recurrence post chemotherapy (19). Recently, we demonstrated that a subset of PvTAMs expressing lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) form a pro-angiogenic Pv niche with a population of pericyte-like cancer associated fibroblasts (CAFs) and orchestrate the platelet-derived growth factor-C (PDGF-C)-dependent expansion of the CAF population with the growing tumor (16). Lyve-1 was traditionally considered a marker of lymphatic endothelium (20), but has emerged as selective marker for a sub-population of Pv tissue-resident macrophages (21)(22)(23)(24)(25) and TAMs (16,26).…”

Section: Introductionmentioning

confidence: 99%

“…Lyve-1 was traditionally considered a marker of lymphatic endothelium (20), but has emerged as selective marker for a sub-population of Pv tissue-resident macrophages (21)(22)(23)(24)(25) and TAMs (16,26). Depleting Lyve-1 + PvTAMs in the spontaneous mouse mammary tumor virus polyomavirus middle T antigen (MMTV-PyMT) murine model of breast cancer using liposome-based approaches resulted in tumor control, highlighting the importance of the TAM subset in cancer progression and formation of the Pv niche (16).…”

Section: Introductionmentioning

confidence: 99%

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Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

Anstee

Opzoomer

Dean

et al. 2022

Preprint

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A subset of tumor associated macrophages (TAMs) identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) reside proximal to blood vasculature and contribute to disease progression. Using a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we show that Lyve-1+ TAMs, which co-express heme oxygenase-1, form coordinated multi-cellular 'nest' structures in the perivascular niche. We show that TAM nest formation is dependent on IL-6 and a communication axis involving CCR5 and its cognate ligands CCL3/4. We demonstrate that Lyve-1+ TAM nests are associated with CD8+ T-cell exclusion from the tumor and the resistance to immune-stimulating chemotherapeutics. This study highlights an unappreciated collaboration between TAMs and uncovers a spatially driven therapeutic resistance mechanism of these cells in cancer which can be therapeutically targeted.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

Anstee

Opzoomer

Dean

et al. 2022

Preprint

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Redox‐Triggered Nanomedicine via Lymphatic Delivery: Inhibition of Melanoma Growth by Ferroptosis Enhancement and a Pt(IV)‐Prodrug Chemoimmunotherapy Approach

Bilbao‐Asensio

Ruiz‐de‐Angulo

Arguinzoniz

et al. 2022

Advanced Therapeutics

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The efficacy of therapies is often hampered by limited tumor drug accumulation achieved through their intravenous administration, and by the lack of selectivity in targeting and killing cancer cells. Amplification of tumor redox stress and ferroptotic cell death to achieve selective killing of cancer cells using iron-containing agents has attracted considerable interest. However, these agents need high doses and multiple injection regimens and have limited success in the treatment of cancers such as melanoma. Melanoma often metastasizes via lymphatic vessels, where the metastasizing cells experience less redox stress and are protected from ferroptosis. Here it is shown that phospholipid-modified Pt(IV) prodrug-loaded iron oxide nanoparticle (IONP)-filled micelles (mIONP-PL-Pt(IV)), which integrate redox reactivity and iron-enabled catalytic therapeutic features with effective nanoparticle-assisted lymphatic delivery, provide significantly enhanced suppression of melanoma tumor growth compared to cisplatin-based chemotherapy and IONP treatments. Peroxidase-like activity, redox-triggered release of cisplatin, and reactivity with hydrogen peroxide and ascorbic acid are contributors toward the induction of a combined ferroptosis-based and cisplatin anti-melanoma treatment. Treatment with mIONP-PL-Pt(IV) provides significant tumor control using cumulative treatment doses 10-100-fold lower than reported in intravenously administered treatments. This work demonstrates the potential of enhancing chemotherapeutic and iron-based catalytic nanomedicine efficacy exploiting nanoparticle-enabled lymphatic trafficking.

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Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

Elfstrum,

Bapat,

Schwertfeger

2024

Cancer Medicine

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IntroductionMacrophages are innate immune cells that are associated with extensive phenotypic and functional plasticity and contribute to normal development, tissue homeostasis, and diseases such as cancer. In this review, we discuss the heterogeneity of tissue resident macrophages in the normal mammary gland and tumor‐associated macrophages in breast cancer. Tissue resident macrophages are required for mammary gland development, where they have been implicated in promoting extracellular matrix remodeling, apoptotic clearance, and cellular crosstalk. In the context of cancer, tumor‐associated macrophages are key drivers of growth and metastasis via their ability to promote matrix remodeling, angiogenesis, lymphangiogenesis, and immunosuppression.MethodWe identified and summarized studies in Pubmed that describe the phenotypic and functional heterogeneity of macrophages and the implications of targeting individual subsets, specifically in the context of mammary gland development and breast cancer. We also identified and summarized recent studies using single‐cell RNA sequencing to identify and describe macrophage subsets in human breast cancer samples.ResultsAdvances in single‐cell RNA sequencing technologies have yielded nuances in macrophage heterogeneity, with numerous macrophage subsets identified in both the normal mammary gland and breast cancer tissue. Macrophage subsets contribute to mammary gland development and breast cancer progression in differing ways, and emerging studies highlight a role for spatial localization in modulating their phenotype and function.ConclusionUnderstanding macrophage heterogeneity and the unique functions of each subset in both normal mammary gland development and breast cancer progression may lead to more promising targets for the treatment of breast cancer.

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Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression

Abstract: Perivascular macrophages orchestrate the expansion of pericyte-like mesenchymal cells to create a proangiogenic niche in cancer.

Cited by 49 publications

References 86 publications

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

Redox‐Triggered Nanomedicine via Lymphatic Delivery: Inhibition of Melanoma Growth by Ferroptosis Enhancement and a Pt(IV)‐Prodrug Chemoimmunotherapy Approach

Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

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