{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:21:19Z","timestamp":1791537679076,"version":"4.3.4"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,18]],"date-time":"2019-04-18T00:00:00Z","timestamp":1555545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["! R01 CA21699 and CA160335"],"award-info":[{"award-number":["! R01 CA21699 and CA160335"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000142","name":"The Avon Foundation for Women","doi-asserted-by":"publisher","award":["02-2016-020 and 02-2017-005"],"award-info":[{"award-number":["02-2016-020 and 02-2017-005"]}],"id":[{"id":"10.13039\/100000142","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"CPRIT","doi-asserted-by":"publisher","award":["RP180734"],"award-info":[{"award-number":["RP180734"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019 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 na\u00efve, 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.<\/jats:p>","DOI":"10.3390\/ijms20081916","type":"journal-article","created":{"date-parts":[[2019,4,18]],"date-time":"2019-04-18T11:58:21Z","timestamp":1555588701000},"page":"1916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":154,"title":["PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS\/Notch\/Nodal Signaling"],"prefix":"10.3390","volume":"20","author":[{"given":"Marc L.","family":"Sprouse","sequence":"first","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Welte","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debasish","family":"Boral","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowen N.","family":"Liu","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yin","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Vishnoi","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debalina","family":"Goswami-Sewell","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Li","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangsheng","family":"Pei","sequence":"additional","affiliation":[{"name":"Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peilin","family":"Jia","sequence":"additional","affiliation":[{"name":"Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella C.","family":"Glitza-Oliva","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Biomarker Research Program Center, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Institute for Academic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1158\/0008-5472.CAN-17-2748","article-title":"Perspective on Circulating Tumor Cell Clusters: Why it takes a village to metastasize","volume":"78","author":"Giuliano","year":"2018","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.cell.2014.07.013","article-title":"Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis","volume":"158","author":"Aceto","year":"2014","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41467-017-00196-1","article-title":"Molecular characterization of breast cancer CTCs associated with brain metastasis","volume":"8","author":"Boral","year":"2017","journal-title":"Nat. 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