PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain un...
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MDPI AG
2019-04-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/20/8/1916 |
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doaj-79c334eacd064d24bb3ff711fdd8717a |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marc L. Sprouse Thomas Welte Debasish Boral Haowen N. Liu Wei Yin Monika Vishnoi Debalina Goswami-Sewell Lili Li Guangsheng Pei Peilin Jia Isabella C. Glitza-Oliva Dario Marchetti |
spellingShingle |
Marc L. Sprouse Thomas Welte Debasish Boral Haowen N. Liu Wei Yin Monika Vishnoi Debalina Goswami-Sewell Lili Li Guangsheng Pei Peilin Jia Isabella C. Glitza-Oliva Dario Marchetti PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling International Journal of Molecular Sciences circulating tumor cells (CTCs) polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs) Heterotypic CTC clusters mutual CTC/PMN-MDSC activation cycle biomarkers and signaling pathways breast cancer melanoma |
author_facet |
Marc L. Sprouse Thomas Welte Debasish Boral Haowen N. Liu Wei Yin Monika Vishnoi Debalina Goswami-Sewell Lili Li Guangsheng Pei Peilin Jia Isabella C. Glitza-Oliva Dario Marchetti |
author_sort |
Marc L. Sprouse |
title |
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling |
title_short |
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling |
title_full |
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling |
title_fullStr |
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling |
title_full_unstemmed |
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling |
title_sort |
pmn-mdscs enhance ctc metastatic properties through reciprocal interactions via ros/notch/nodal signaling |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-04-01 |
description |
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease. |
topic |
circulating tumor cells (CTCs) polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs) Heterotypic CTC clusters mutual CTC/PMN-MDSC activation cycle biomarkers and signaling pathways breast cancer melanoma |
url |
https://www.mdpi.com/1422-0067/20/8/1916 |
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doaj-79c334eacd064d24bb3ff711fdd8717a2020-11-25T02:16:03ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-04-01208191610.3390/ijms20081916ijms20081916PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal SignalingMarc L. Sprouse0Thomas Welte1Debasish Boral2Haowen N. Liu3Wei Yin4Monika Vishnoi5Debalina Goswami-Sewell6Lili Li7Guangsheng Pei8Peilin Jia9Isabella C. Glitza-Oliva10Dario Marchetti11Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USACenter for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USACenter for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USADepartment of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USABiomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USAIntratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.https://www.mdpi.com/1422-0067/20/8/1916circulating tumor cells (CTCs)polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs)Heterotypic CTC clustersmutual CTC/PMN-MDSC activation cyclebiomarkers and signaling pathwaysbreast cancermelanoma |