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.
Highlights
It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, in vivo steps and molecular mechanisms are poorly elucidated
Using co-culture experiments, we show that tumour-infiltrated mMDSCs from 4T1 tumour-bearing mice induce epithelial– mesenchymal transition (EMT)/cancer stem cell (CSC) phenotype, while gMDSCs from lungs suppress EMT/CSC phenotype and promote cell proliferation
We demonstrate that early infiltration of mMDSCs within primary tumours and a gradual increase of gMDSCs by week 4 was detected in the 4T1 tumours (Fig. 2a,b)
Summary
It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, in vivo steps and molecular mechanisms are poorly elucidated. Advanced studies in recent decades reframed the ‘seed and soil’ concept in a modern context by which successful metastases require that developing malignant cells eliminate anti-tumour responses, a small subset of (disseminating) cells -‘seed’- undergo epithelial– mesenchymal transition (EMT) leading to cancer stem cell (CSC) phenotype and remotely generate a supportive microenvironment -‘soil’- in distant tissues[7,8]. A dynamic and reversible transitions between EMT and MET state has been shown to be critical processes in driving squamous cell carcinoma metastasis[9] Consistent with this notion, EMT signature alone fails to predict metastasis in majority of malignancies[7,10,11]. Myeloid-derived suppressor cells (MDSC) were initially identified in cancer patients and mouse models due to their potent immunesuppressive activity, they are being implicated in the promotion of tumour metastasis by participating in the formation of pre-metastatic niches, angiogenesis and invasion[13]. A ‘metastatic gene signature’ identified in a murine model predict poor patient survival human malignancies suggesting clinical relevance of our data in mouse models
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
