Immune regulation of tumor cell plasticity: A promising molecular target in breast cancer metastasis

Hdl Handle:
http://hdl.handle.net/10675.2/621941
Title:
Immune regulation of tumor cell plasticity: A promising molecular target in breast cancer metastasis
Authors:
LEE, EUNMI
Abstract:
It is widely accepted that phenotypic plasticity of malignant cells is required during metastatic cascade. However, the specific mechanism of how the tumor microenvironment regulates tumor cell plasticity in metastasis is under intense investigation. We demonstrate here that monocytic and granulocytic subsets of myeloid-derived suppressor cells (MDSC), hereafter called mMDSCs and gMDSCs, infiltrate in the primary tumor and distant organs with different time kinetics and regulate spatiotemporal tumor plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumor-infiltrating mMDSCs facilitate dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support metastatic growth by reverting the EMT/CSC phenotype and promoting tumor cell proliferation. We also observe that lung-derived gMDSCs isolated from tumor-bearing mice enhance metastatic growth of already disseminated tumor cells. Our ongoing studies reveal that calprotectin (S100A8 and S100A9 heterotetramer) is an important regulator of gMDSCs, which play a critical role in promoting breast cancer metastasis by inducing MET-like CSCs as well as suppressing anti-tumor immunity within the pre-metastatic niche. Furthermore, we develop a novel gMDSC-targeting compound that potentially binds to calprotectin and validate its therapeutic utility in a preclinical breast cancer model. Our goal for this study is to elucidate the molecular co-evolution of tumor and immune cells in cancer development and to identify molecular targets to provide alternative therapeutic options for women with metastatic disease.
Advisors:
Korkaya, Hasan
Affiliation:
Department of Biochemistry and Molecular Biology / Cancer Center
Issue Date:
29-Nov-2018
URI:
http://hdl.handle.net/10675.2/621941
Type:
Dissertation
Description:
Record is embargoed until 11/29/2019
Appears in Collections:
Department of Biochemistry and Molecular Biology Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.advisorKorkaya, Hasanen
dc.contributor.authorLEE, EUNMIen
dc.date.accessioned2018-11-29T17:02:37Z-
dc.date.available2019-11-29T17:02:37Z-
dc.date.issued2018-11-29-
dc.identifier.urihttp://hdl.handle.net/10675.2/621941-
dc.descriptionRecord is embargoed until 11/29/2019en
dc.description.abstractIt is widely accepted that phenotypic plasticity of malignant cells is required during metastatic cascade. However, the specific mechanism of how the tumor microenvironment regulates tumor cell plasticity in metastasis is under intense investigation. We demonstrate here that monocytic and granulocytic subsets of myeloid-derived suppressor cells (MDSC), hereafter called mMDSCs and gMDSCs, infiltrate in the primary tumor and distant organs with different time kinetics and regulate spatiotemporal tumor plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumor-infiltrating mMDSCs facilitate dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support metastatic growth by reverting the EMT/CSC phenotype and promoting tumor cell proliferation. We also observe that lung-derived gMDSCs isolated from tumor-bearing mice enhance metastatic growth of already disseminated tumor cells. Our ongoing studies reveal that calprotectin (S100A8 and S100A9 heterotetramer) is an important regulator of gMDSCs, which play a critical role in promoting breast cancer metastasis by inducing MET-like CSCs as well as suppressing anti-tumor immunity within the pre-metastatic niche. Furthermore, we develop a novel gMDSC-targeting compound that potentially binds to calprotectin and validate its therapeutic utility in a preclinical breast cancer model. Our goal for this study is to elucidate the molecular co-evolution of tumor and immune cells in cancer development and to identify molecular targets to provide alternative therapeutic options for women with metastatic disease.en
dc.subjectBreast Canceren
dc.subjectMetastasisen
dc.subjectEMTen
dc.subjectMETen
dc.subjectCSCen
dc.subjectMyeloid-derived suppressor cellen
dc.subjectImmunosuppressionen
dc.subjectPro-metastatic nicheen
dc.titleImmune regulation of tumor cell plasticity: A promising molecular target in breast cancer metastasisen
dc.typeDissertationen
dc.contributor.departmentDepartment of Biochemistry and Molecular Biology / Cancer Centeren
dc.language.rfc3066en-
dc.date.updated2018-11-29T17:02:37Z-
dc.description.committeeArbab, Ali; Bollag, Wendy; Liu, Kebin; Zhou, Gangen
dc.description.degreeDoctor of Philosophy with a Major in Biochemistry and Cancer Biologyen
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