The Protease-Dependent Mesenchymal Migration of Tumor-Associated Macrophages as a Target in Cancer Immunotherapy

Gui, Philippe; Ben-Neji, Myriam; Belozertseva, Ekaterina; Dalenc, Florence; Franchet, Camille; Gilhodes, Julia; Labrousse, Arnaud; Bellard, Elisabeth; Golzio, Muriel; Poincloux, Renaud; Maridonneau‐Parini, Isabelle; Cabec, Véronique Le

doi:10.1158/2326-6066.cir-17-0746

Cited by 31 publications

(65 citation statements)

References 55 publications

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“…Therefore, migration of Hoxb8-macrophages matches characteristics of mesenchymal and amoeboid migration when migrating in 3D in Matrigel and fibrillar collagen respectively, with regard to cell morphology, cell dynamic and drug responsiveness (Gui et al, 2018;Van Goethem et al, 2010).…”

Section: Hoxb8-macrophagesmentioning

confidence: 72%

“…Mice and human macrophage mesenchymal migration in Matrigel depends on protease activity and is therefore inhibited by a mix of proteases inhibitors (PI mix) (Gui et al, 2018;Gui et al, 2014;Guiet et al, 2011;Jevnikar et al, 2012;Van Goethem et al, 2010). In contrast, amoeboid migration in fibrillar collagen is dependent on the Rho/ROCK pathway and is therefore inhibited by the ROCK inhibitor Y-27632 (Gui et al, 2018;Gui et al, 2014;Jevnikar et al, 2012;Van Goethem et al, 2010). To ascertain that Hoxb8macrophages used the mesenchymal migration in Matrigel and the amoeboid migration in fibrillar collagen, as expected for macrophages, PI mix or Y-27632 were used in the migration assay.…”

Section: Hoxb8-macrophagesmentioning

confidence: 99%

“…The movement is slow and directional, involves cell adhesion to the substratum, and requires proteases to degrade the ECM in order to create paths through dense environments. In both human and mouse macrophages, this migration is dependent on podosomes and is not inhibited but rather stimulated by treatment with ROCK inhibitors (Gui et al, 2018;Gui et al, 2014). It has been shown in vitro that, in contrast to lymphocytes, neutrophils and monocytes Friedl and Weigelin, 2008;Lammermann and Germain, 2014), tumor cells or immature human dendritic cells (DCs) can perform these two mechanistically distinct migration modes (Cougoule et al, 2018;Friedl and Wolf, 2003;Sahai and Marshall, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown in vitro that, in contrast to lymphocytes, neutrophils and monocytes Friedl and Weigelin, 2008;Lammermann and Germain, 2014), tumor cells or immature human dendritic cells (DCs) can perform these two mechanistically distinct migration modes (Cougoule et al, 2018;Friedl and Wolf, 2003;Sahai and Marshall, 2003). Human and mouse macrophages can also adopt these two migration modes depending on the ECM architecture (Barros-Becker et al, 2017;Cermak et al, 2018;Cougoule et al, 2010;Cougoule et al, 2012;Gui et al, 2018;Gui et al, 2014;Guiet et al, 2012;Jevnikar et al, 2012;Maridonneau-Parini, 2014;Van Goethem et al, 2011;Van Goethem et al, 2010;Verollet et al, 2011;Verollet et al, 2015). In vivo in mouse tumors and ex vivo in human breast cancer explants, TAM use the protease-dependent mesenchymal migration mode.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo in mouse tumors and ex vivo in human breast cancer explants, TAM use the protease-dependent mesenchymal migration mode. At the tumor periphery or in inflamed ear derma in mice, macrophages use the amoeboid motility (Gui et al, 2018). Inhibition of matrix metalloproteases (MMPs) blocked the mesenchymal migration of human macrophages ex vivo and mice macrophages in vivo, which correlates with a decrease in both macrophage infiltration into tumors and tumor growth in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Genetic engineering of hoxb8 immortalized hematopoietic progenitors: a potent tool to study macrophage tissue migration

Accarias

Sanchez

Labrousse

et al. 2019

Preprint

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statement:We validate the use of ER-Hoxb8-immortalized hematopoietic progenitors combined to CRISPR/Cas9 technology as a potent tool to investigate macrophage functionalities with a large scale of applications. Abstract:Tumor-associated macrophages (TAM) are detrimental in most cancers. Controlling their recruitment is thus potentially therapeutic. We showed that TAM perform the proteasedependent mesenchymal migration in cancer, while macrophages perform amoeboid migration in other tissues. Inhibition of mesenchymal migration correlates with decreased TAM infiltration and tumor growth, providing rationale for a new cancer immunotherapy specifically targeting TAM motility. To identify new effectors of mesenchymal migration, we produced ER-Hoxb8-immortalized hematopoietic progenitors with unlimited proliferative ability. The functionality of macrophages differentiated from ER-Hoxb8 progenitors was compared to bone marrow-derived macrophages (BMDM). They polarized into M1-and M2-orientated macrophages, generated ROS, ingested particles, formed podosomes, degraded the extracellular matrix, adopted amoeboid and mesenchymal migration in 3D, and infiltrated tumor explants ex vivo using mesenchymal migration. We also used the CRISPR/Cas9 system to disrupt gene expression of a known effector of mesenchymal migration, WASP, to provide a proof of concept. We observed impaired podosome formation and mesenchymal migration capacity, thus recapitulating the phenotype of BMDM isolated from Wasp-KO mice. Thus, we validate the use of Hoxb8-macrophages as a potent tool to investigate macrophage functionalities.

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Section: Hoxb8-macrophagesmentioning

confidence: 72%

Section: Hoxb8-macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic engineering of hoxb8 immortalized hematopoietic progenitors: a potent tool to study macrophage tissue migration

Accarias

Sanchez

Labrousse

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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Gelatin‐Hyaluronan Click‐Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior

Bahlmann

Baker

Xue

et al. 2021

Adv Funct Materials

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Hydrogel models of metastasis traditionally focus on the invasion of cancer cells; however, other cells in the tumor microenvironment that are associated with metastasis also have the ability to migrate. Macrophage phenotype plays a key role in the tumor microenvironment, yet understanding their migration within tunable 3D in vitro models has been limited. To gain a greater understanding of macrophage invasive behavior, stable and transparent oxime‐crosslinked cryogels comprised of click‐crosslinked gelatin‐oxyamine and hyaluronan‐aldehyde (GELox‐HAa) are synthesized. Fibronectin‐derived, oxyamine‐modified PHSRN‐RGDSP peptides are incorporated to further mimic the tumor extracellular matrix without impacting cryogel mechanics. It is found that primary human macrophages migrate to a greater depth in cryogels with greater porosity and pore size. To better understand the mechanism of migration, cells are treated with either inhibitors of matrix metalloproteinases (MMPs) or rho‐associated protein kinase (ROCK) and a predominantly MMP‐mediated mechanism of invasion is found. Macrophage polarization studies reveal that anti‐inflammatory, interleukin‐4/13 (IL4/IL13)‐treated macrophages migrate through cryogels to a greater extent than pro‐inflammatory, interferon‐gamma/lipopolysaccharide (IFNγ/LPS)‐treated cells. Interestingly, polarized macrophages move through cryogels using a combination of amoeboid and mesenchymal migration. These findings of macrophage invasion in this cryogel platform set the stage for their further study in a biomimetic tumor microenvironment.

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Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

Gong

et al. 2020

Advanced Therapeutics

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Tumor-associated macrophages (TAMs), one of the most important constituents in tumor immunosuppressive microenvironments, are a potential therapeutic target due to their essential role in promoting tumor progression and metastasis. Macrophages are usually divided into two categories of protumoral M2-like TAMs and antitumoral M1 phenotypes at the two extremes. Reprogramming M2-like TAMs toward tumoricidal M1 phenotype is especially intriguing in terms of the restoration of antitumor immunity for anticancer immunotherapy. In this review, the recent advances of nanomedicine-mediated reprogramming of TAMs from M2 to M1 to elicit the antitumor immunity are discussed. This reprogramming can be achieved via direct re-education by targeted delivery of various active agents to TAMs and indirect re-education by modulating the abnormal tumor microenvironment. Perspectives on nanomedicine mediated TAMs-M1 reprogramming for effective anticancer immunotherapy are also presented.

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The Protease-Dependent Mesenchymal Migration of Tumor-Associated Macrophages as a Target in Cancer Immunotherapy

Cited by 31 publications

References 55 publications

Genetic engineering of hoxb8 immortalized hematopoietic progenitors: a potent tool to study macrophage tissue migration

Genetic engineering of hoxb8 immortalized hematopoietic progenitors: a potent tool to study macrophage tissue migration

Gelatin‐Hyaluronan Click‐Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

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