Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy

Parsons, Tyler; Buelow, Katie L.; Hanna, Alaa; Brake, Marisa A; Poma, Crystal; Hosch, Sarah E.; Westrick, Randal J.; Villa‐Diaz, Luis G.; Wilson, George; Madlambayan, Gerard J.

doi:10.1038/s41416-021-01652-y

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…For GW2580, pretreatment of mice before implantation of U251 glioma cells resulted in a decreased number of intratumoral myeloid cells and improved tumor control 58 . However, how GW2580 affects the growth of an already established glioma is not known thus far, but there are promising data from other xenotransplantation models, such as melanoma, hepatocellular carcinoma, and non-small cell lung cancer, describing reduced tumor growth and downregulation of anti-inflammatory M2-like tumor-associated macrophages upon treatment with GW2580 [59][60][61] . Clinically, in addition to many other tumor types, PLX3397 has been administered in a phase II trial to patients suffering from recurrent GBM and in a phase Ib/II trial to newly diagnosed GBM patients combined with radiochemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Fermi

Warta

Rapp

et al. 2022

Preprint

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Targeting immunosuppressive and protumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) holds great potential to improve patient outcomes. Although CSF1R has emerged as a promising target to reprogram anti-inflammatory M2-like GAMs, relevant treatment data on human, tumor-educated GAMs and innovative patient-derived 3D tumor organoid models to study the influence on adaptive immunity and the effectiveness of treatment in a complex and entirely autologous setting are largely lacking. We performed a comprehensive phenotypical, transcriptional and functional analysis of primary, patient-derived GAMs upon treatment with the CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to a downregulation of M2-related markers and signaling pathways, while M1-like markers, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming together with reduced tumor cell proliferation, indicating that treatment with GW2580 could be an important pillar in the future therapy of GBM.

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Section: Discussionmentioning

confidence: 99%

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Fermi

Warta

Rapp

et al. 2022

Preprint

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“…For example, radiation exposure causes myelosuppression due to the lack of function of hematopoietic stem/progenitor cells (HSPCs) during radiotherapy and a nuclear disaster 4 . Moreover, recent reports have shown that HSPCs localize within the tumor microenvironment and facilitate tumor growth 5 . These reports suggest that it is important to understand the functional mechanism and reaction of HSPCs to stress stimuli.…”

Section: Introductionmentioning

confidence: 99%

Prediction of hub genes and key pathways associated with the radiation response of human hematopoietic stem/progenitor cells using integrated bioinformatics methods

Sato

Yoshino

Ishikawa

et al. 2023

Sci Rep

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Hematopoietic stem cells (HSCs) are indispensable for the maintenance of the entire blood program through cytokine response. However, HSCs have high radiosensitivity, which is often a problem during radiation therapy and nuclear accidents. Although our previous study has reported that the combination cytokine treatment (interleukin-3, stem cell factor, and thrombopoietin) improves the survival of human hematopoietic stem/progenitor cells (HSPCs) after radiation, the mechanism by which cytokines contribute to the survival of HSPCs is largely unclear. To address this issue, the present study characterized the effect of cytokines on the radiation-induced gene expression profile of human CD34+ HSPCs and explored the hub genes that play key pathways associated with the radiation response using a cDNA microarray, a protein–protein interaction-MCODE module analysis and Cytohubba plugin tool in Cytoscape. This study identified 2,733 differentially expressed genes (DEGs) and five hub genes (TOP2A, EZH2, HSPA8, GART, HDAC1) in response to radiation in only the presence of cytokines. Furthermore, functional enrichment analysis found that hub genes and top DEGs based on fold change were enriched in the chromosome organization and organelle organization. The present findings may help predict the radiation response and improve our understanding of this response of human HSPCs.

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“…M1-polarized macrophages, also known as classical activated macrophages, routinely exert anti-cancerous effects [ 13 , 14 ]. M2-polarized macrophages, also known as alternatively activated macrophage, routinely exert tumor-promoting effects [ 12 , 15 , 16 ]. Results from an increasing number of investigations suggest that TAMs resemble M2-polarized macrophages [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

LARRPM restricts lung adenocarcinoma progression and M2 macrophage polarization through epigenetically regulating LINC00240 and CSF1

Chen

Liu

et al. 2022

Cell Mol Biol Lett

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Background Long non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the involvement of lncRNAs in TAM activation is still largely unknown. Methods The expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA–protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM. Results The lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene LINC00240, leading to a decrease in DNA methylation level of the LINC00240 promoter and transcriptional activation of LINC00240. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the CSF1 promoter, resulting in increased DNA methylation of the CSF1 promoter and transcriptional repression of CSF1, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells. Conclusions LARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.

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Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy

Cited by 5 publications

References 35 publications

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Prediction of hub genes and key pathways associated with the radiation response of human hematopoietic stem/progenitor cells using integrated bioinformatics methods

LARRPM restricts lung adenocarcinoma progression and M2 macrophage polarization through epigenetically regulating LINC00240 and CSF1

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