Immune regulation of metastasis: mechanistic insights and therapeutic opportunities

Blomberg, Olga; Spagnuolo, Lorenzo; Visser, Karin E. de

doi:10.1242/dmm.036236

Cited by 107 publications

(89 citation statements)

References 199 publications

(221 reference statements)

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“…Five genes with known roles in regulating immune cell function were identified; the immune cell types included NK cells, lymphocytes (T-and B-cells) and granulocytes/macrophages, which have all been shown to play critical roles in regulating metastasis (reviewed in (Blomberg et al 2018)). Thus genes that interfere with their production, maturation and/or function could understandably result in increased levels of metastatic colonisation.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation

Weyden

Swiatkowska

Iyer

et al. 2020

Preprint

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ABSTRACTMetastatic colonisation, whereby a disseminated tumour cell is able to survive and proliferate at a secondary site, involves both tumour cell-intrinsic and -extrinsic factors. To identify tumour cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumour cells to effectively colonise a tissue, we performed a genome-wide screen utilising the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonisation (15 increased and 19 decreased; P<0.005 and genotype effect <-60 or >+60). Whilst several of these genes have known roles in immune system regulation (Bach2, Cyba, Cybb, Cybc1, Id2, Igh-6, Irf1, Irf7, Ncf1, Ncf2, Ncf4 and Pik3cg) most are involved in a disparate range of biological processes, ranging from ubiquitination (Herc1) to diphthamide synthesis (Dph6) to Rho GTPase-activation (Arhgap30 and Fgd4), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonisation, which may represent potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation

Weyden

Swiatkowska

Iyer

et al. 2020

Preprint

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“…Interestingly, the variance in gene expression observed between these routes of implantation implicated immune interaction as a key distinguishing factor. It is now widely accepted that factors released from the primary tumor prepare the secondary organ, and altered immune infiltration is a major aspect of this niche formation 22,23,[34][35][36] . Based on our data, we hypothesize that the pre-metastatic niche may be key in shaping the MSGE of some cell lines when used in allograft models.…”

Section: Discussionmentioning

confidence: 99%

Metastasis-specific gene expression in autochthonous and allograft mouse mammary tumor models: stratification and identification of targetable signatures

Ross

Szczepanek

Lee

et al. 2019

Preprint

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Breast cancer is a leading cause of cancer-related death of women in the U.S., which is ultimately due to metastasis rather than primary tumor burden. Therefore, increased understanding of metastasis to develop novel therapies is critical in reducing breast cancer-related mortality. Indeed, a major hurdle in advancing metastasis-targeted intervention is the genotypic and phenotypic heterogeneity that exists between primary and secondary lesions. To identify targetable metastasis-specific gene expression profiles we performed RNA sequencing of breast cancer metastasis mouse models. We analyzed metastases from models of various oncogenic drivers and routes, including orthotopic injection, tail vein injection, intracardiac injection, and genetically engineered mouse models (GEMMs). Herein, we analyzed samples from 176 mice and tissue culture samples, resulting in 338 samples total. Using these data, we contrasted the different breast cancer metastasis models, and also identified common, targetable metastasis specific gene expression signatures.Principal component analysis revealed that mouse model (Allograft v. GEMM) rather than tissue source (PT v metastatic nodule) shaped the transcriptomes of our samples. Allograft models exhibited more mesenchymal-like gene expression than GEMM models, and primary culturing of GEMM-derived metastatic tissue induced more mesenchymallike gene expression. Furthermore, metastasis-specific gene expression differed between tail vein and orthotopic injection models of the same cell line, the degree of which was cell line dependent. Finally, we examined metastasis-specific gene expression common to models of spontaneous metastasis (orthotopic injection and GEMMs). Pathway analysis identified upregulation of the sildenafil response, and nicotine degradation pathways. The influence of these pathways on metastatic spread was assessed by treatment of allograft models with clinically relevant dosing of sildenafil or nicotine. Sildenafil significantly reduced pulmonary metastasis while nicotine administration significantly increased metastasis, and neither regimen altered primary tumor mass. Taken together our data reveals critical differences between pre-clinical models of metastatic breast cancer. Additionally, this strategy has identified clinically targetable metastasis-specific pathways integral to metastatic spread.

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“…Theorem 2 For sufficiently small > 0, the dynamics of the reduced system (8) on the slow manifold M provide a reasonable approximation (in the sense of Theorem 1) of the full system (4).…”

Section: Propositionmentioning

confidence: 97%

“…Not only have pro-tumor immune effects been observed at each step of the metastatic cascade [37,47,49], but tumor-mediated immune cell phenotypic plasticity has also been documented [10,15,33,39,49], significantly complicating potential immune-based therapeutic interventions [47] and suggesting that metastasis may be more organized than previously thought. For further details concerning the immune mediated theory of metastasis, or immune involvement in metastasis more generally, please consult one of [4,9,37,47,49].…”

Section: Immune-mediated Theory Of Metastasismentioning

confidence: 99%

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

Rhodes

Hillen

2019

Preprint

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Metastatic seeding of distant organs can occur in the very early stages of primary tumor development. Once seeded, these micrometastases may enter a dormant phase that can last decades. Curiously, the surgical removal of the primary tumor can stimulate the accelerated growth of distant metastases, a phenomenon known as metastatic blow-up. Although several theories have been proposed to explain metastatic dormancy and blow-up, most mathematical investigations have ignored the important pro-tumor effects of the immune system. In this work, we address that shortcoming by developing an ordinary differential equation model of the immune-mediated theory of metastasis. We include both anti-and pro-tumor immune effects, in addition to the experimentally observed phenomenon of tumor-induced immune cell phenotypic plasticity. Using geometric singular perturbation analysis, we derive a rather simple model that captures the main processes and, at the same time, can be fully analyzed. Literature-derived parameter estimates are obtained, and model robustness is demonstrated through a sensitivity analysis. We determine conditions under which the parameterized model can successfully explain both metastatic dormancy and blow-up. Numerical simulations suggest a novel measure to predict the occurrence of future metastatic blow-up, in addition to new potential avenues for treatment of clinically undetectable micrometastases.Keywords Mathematical oncology · Cancer modeling · Metastasis · Dormancy · Geometric singular perturbation analysis · Ordinary differential equations Immune-Mediated Metastasis 7 The Reduced Immune-Mediated Metastasis ModelCompared to the original model from [47] we make the following simplifying assumptions.

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Immune regulation of metastasis: mechanistic insights and therapeutic opportunities

Cited by 107 publications

References 199 publications

A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation

A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation

Metastasis-specific gene expression in autochthonous and allograft mouse mammary tumor models: stratification and identification of targetable signatures

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

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