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Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade

View Article: PubMed Central - PubMed

ABSTRACT

It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced ‘metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

No MeSH data available.


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Lung-derived gMDSCs promote tumour cell proliferation via induction of a distinct gene expression signature called metastatic gene signature.(a,b) Tumour cell proliferation was enhanced when they were co-cultured with lung- or tumour-derived gMDSCs compared to BM-derived mMDSCs and gMDSCs under serum-free culture condition. (c) There was also upregulation of EpCAM expression in tumour cells when they were co-cultured with lung-derived gMDSCs. (d,e) There are over 750 genes that are differentially regulated in tumour cells when co-cultured with gMDSCs either from BM or lungs of 4T1 tumour-bearing mice. (f) Top genes, highly upregulated in tumour cells upon co-culture with BM- or lung-derived gMDSCs are listed with their fold increase. We called 8 genes (indicated by red colour) ‘metastatic gene signature' since they were distinctly upregulated by lung-derived gMDSCs. (g–j) Upregulations of these genes as well as the proliferation marker PCNA were verified by qPCR in both 4T1 tumour-bearing BALB/c and AT-3 tumour-bearing C57BL/6J mouse models. Results are presented as mean±s.d. (n=3). Scale bar, 50 μm; *P<0.05, **P<0.005, ***P<0.0005 unpaired t-test.
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f6: Lung-derived gMDSCs promote tumour cell proliferation via induction of a distinct gene expression signature called metastatic gene signature.(a,b) Tumour cell proliferation was enhanced when they were co-cultured with lung- or tumour-derived gMDSCs compared to BM-derived mMDSCs and gMDSCs under serum-free culture condition. (c) There was also upregulation of EpCAM expression in tumour cells when they were co-cultured with lung-derived gMDSCs. (d,e) There are over 750 genes that are differentially regulated in tumour cells when co-cultured with gMDSCs either from BM or lungs of 4T1 tumour-bearing mice. (f) Top genes, highly upregulated in tumour cells upon co-culture with BM- or lung-derived gMDSCs are listed with their fold increase. We called 8 genes (indicated by red colour) ‘metastatic gene signature' since they were distinctly upregulated by lung-derived gMDSCs. (g–j) Upregulations of these genes as well as the proliferation marker PCNA were verified by qPCR in both 4T1 tumour-bearing BALB/c and AT-3 tumour-bearing C57BL/6J mouse models. Results are presented as mean±s.d. (n=3). Scale bar, 50 μm; *P<0.05, **P<0.005, ***P<0.0005 unpaired t-test.

Mentions: We next examined the effect of MDSC subsets on tumour cell growth under in vitro co-culture conditions. Since 4T1 tumours develop spontaneous pulmonary metastasis in 100% of animals and show infiltration of gMDSCs in lungs 3 weeks post implantation, we reasoned that lung-infiltrated gMDSCs might support metastatic growth. To test this hypothesis, EMT6 tumour cells were co-cultured with mMDSC or gMDSCs from bone marrow (BM), tumour or lungs of 4T1 tumour-bearing mice. While tumour cell proliferation is enhanced by gMDSCs derived from lungs (60%) or tumour (40%), in contrast, bone-marrow-derived mMDSC or gMDSCs failed to do so (Fig. 6a,b). Lung-derived gMDSCs also enhanced the expression of EpCAM in tumour cells in co-culture experiments (Fig. 6c). We further confirmed that lung-derived gMDSCs from 4T1 tumour-bearing mice were more effective in promoting tumour cell proliferation compared to the gMDSCs from EMT6 tumour-bearing mice (Supplementary Fig. 6a,b).


Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade
Lung-derived gMDSCs promote tumour cell proliferation via induction of a distinct gene expression signature called metastatic gene signature.(a,b) Tumour cell proliferation was enhanced when they were co-cultured with lung- or tumour-derived gMDSCs compared to BM-derived mMDSCs and gMDSCs under serum-free culture condition. (c) There was also upregulation of EpCAM expression in tumour cells when they were co-cultured with lung-derived gMDSCs. (d,e) There are over 750 genes that are differentially regulated in tumour cells when co-cultured with gMDSCs either from BM or lungs of 4T1 tumour-bearing mice. (f) Top genes, highly upregulated in tumour cells upon co-culture with BM- or lung-derived gMDSCs are listed with their fold increase. We called 8 genes (indicated by red colour) ‘metastatic gene signature' since they were distinctly upregulated by lung-derived gMDSCs. (g–j) Upregulations of these genes as well as the proliferation marker PCNA were verified by qPCR in both 4T1 tumour-bearing BALB/c and AT-3 tumour-bearing C57BL/6J mouse models. Results are presented as mean±s.d. (n=3). Scale bar, 50 μm; *P<0.05, **P<0.005, ***P<0.0005 unpaired t-test.
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f6: Lung-derived gMDSCs promote tumour cell proliferation via induction of a distinct gene expression signature called metastatic gene signature.(a,b) Tumour cell proliferation was enhanced when they were co-cultured with lung- or tumour-derived gMDSCs compared to BM-derived mMDSCs and gMDSCs under serum-free culture condition. (c) There was also upregulation of EpCAM expression in tumour cells when they were co-cultured with lung-derived gMDSCs. (d,e) There are over 750 genes that are differentially regulated in tumour cells when co-cultured with gMDSCs either from BM or lungs of 4T1 tumour-bearing mice. (f) Top genes, highly upregulated in tumour cells upon co-culture with BM- or lung-derived gMDSCs are listed with their fold increase. We called 8 genes (indicated by red colour) ‘metastatic gene signature' since they were distinctly upregulated by lung-derived gMDSCs. (g–j) Upregulations of these genes as well as the proliferation marker PCNA were verified by qPCR in both 4T1 tumour-bearing BALB/c and AT-3 tumour-bearing C57BL/6J mouse models. Results are presented as mean±s.d. (n=3). Scale bar, 50 μm; *P<0.05, **P<0.005, ***P<0.0005 unpaired t-test.
Mentions: We next examined the effect of MDSC subsets on tumour cell growth under in vitro co-culture conditions. Since 4T1 tumours develop spontaneous pulmonary metastasis in 100% of animals and show infiltration of gMDSCs in lungs 3 weeks post implantation, we reasoned that lung-infiltrated gMDSCs might support metastatic growth. To test this hypothesis, EMT6 tumour cells were co-cultured with mMDSC or gMDSCs from bone marrow (BM), tumour or lungs of 4T1 tumour-bearing mice. While tumour cell proliferation is enhanced by gMDSCs derived from lungs (60%) or tumour (40%), in contrast, bone-marrow-derived mMDSC or gMDSCs failed to do so (Fig. 6a,b). Lung-derived gMDSCs also enhanced the expression of EpCAM in tumour cells in co-culture experiments (Fig. 6c). We further confirmed that lung-derived gMDSCs from 4T1 tumour-bearing mice were more effective in promoting tumour cell proliferation compared to the gMDSCs from EMT6 tumour-bearing mice (Supplementary Fig. 6a,b).

View Article: PubMed Central - PubMed

ABSTRACT

It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced &lsquo;metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

No MeSH data available.


Related in: MedlinePlus