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Microtentacle-Mediated Heterotypic Clustering of Tumor Cells and Neutrophils in Breast Cancer Metastasis
Microtentacle-Mediated Heterotypic Clustering of Tumor Cells and Neutrophils in Breast Cancer Metastasis
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104640
- ISBN
- 9798290940137
- DDC
- 616.99
- 저자명
- Ju, Julia A.
- 서명/저자
- Microtentacle-Mediated Heterotypic Clustering of Tumor Cells and Neutrophils in Breast Cancer Metastasis
- 발행사항
- [Sl] : University of Maryland, Baltimore, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 253 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Martin, Stuart S.
- 학위논문주기
- Thesis (Ph.D.)--University of Maryland, Baltimore, 2025.
- 초록/해제
- 요약Current cancer therapies are mainly used clinically to target the growth of the primary tumor, even though metastasis is what ultimately leads to patient mortality. Circulating tumor cells (CTCs) and CTC clusters are found in the blood of cancer patients and serve as direct precursors of metastatic outgrowth for many solid tumors, including breast cancer. Before tumor cells can colonize at distant metastatic sites, however, they encounter and engage with a variety of immune cells throughout the bloodstream, which ultimately can regulate tumor progression. Heterotypic cell clusters form between CTCs and white blood cells (WBCs) and recent studies report that a majority of these WBCs are neutrophils in patient and mouse models. Even though CTC clusters only encompass a small fraction (3- 6%) of total CTC events found in the blood vasculature, they have a 25-50x higher metastatic potential and are associated with decreased overall survival in patients compared to single CTCs. Our lab discovered that CTCs produce tubulin-based protrusions, microtentacles (McTNs), which promote reattachment, retention in distant sites during metastasis and formation of tumor cell clusters. Neutrophil-CTC clusters help CTCs survive the harsh vascular environment to promote successful metastasis, however, the specific mechanism of this interaction is not fully understood. Utilizing TetherChip technology to recapitulate the nonadherent environments of metastasis, we found that primary and differentiated neutrophils produce McTNs composed of detyrosinated and acetylated α-tubulin and vimentin. Differentiation into neutrophils induced homotypic cluster formation, migration, and reattachment to fibronectin, which were all suppressed with the tubulin-depolymerizing agent, Vinorelbine. Neutrophil McTNs could also be targeted with tubulin-modulating chemotherapeutics such as Tetracaine, Paclitaxel and Cytochalasin D. Co-culturing differentiated neutrophils and tumor cells formed heterotypic clusters that enhanced migration toward multiple stimuli and Vinorelbine treatment reduced this heterotypic clustering efficiency as well as co-culture migration. Finally, differentially expressed cytokines were present in the co-culture between tumor cells and neutrophils and high expression of these signaling molecules were associated with worse prognosis in patients with breast cancer. CTC-neutrophil clusters have higher metastatic efficiency, and by demonstrating that neutrophils form McTNs, we reveal a new possible mechanism for how neutrophils interact with tumor cells. These findings further support the idea that developing cluster-disrupting therapies could provide a new targeted strategy to reduce the metastatic potential of cancer cells and yield more successful clinical outcomes.
- 일반주제명
- Oncology
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 키워드
- Metastasis
- 키워드
- Neutrophils
- 기타저자
- University of Maryland, Baltimore Molecular Medicine
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104640
■006m o d
■007cr#unu||||||||
■020 ▼a9798290940137
■035 ▼a(MiAaPQ)AAI32113935
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.99
■1001 ▼aJu, Julia A.
■24510▼aMicrotentacle-Mediated Heterotypic Clustering of Tumor Cells and Neutrophils in Breast Cancer Metastasis
■260 ▼a[Sl]▼bUniversity of Maryland, Baltimore▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a253 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Martin, Stuart S.
■5021 ▼aThesis (Ph.D.)--University of Maryland, Baltimore, 2025.
■520 ▼aCurrent cancer therapies are mainly used clinically to target the growth of the primary tumor, even though metastasis is what ultimately leads to patient mortality. Circulating tumor cells (CTCs) and CTC clusters are found in the blood of cancer patients and serve as direct precursors of metastatic outgrowth for many solid tumors, including breast cancer. Before tumor cells can colonize at distant metastatic sites, however, they encounter and engage with a variety of immune cells throughout the bloodstream, which ultimately can regulate tumor progression. Heterotypic cell clusters form between CTCs and white blood cells (WBCs) and recent studies report that a majority of these WBCs are neutrophils in patient and mouse models. Even though CTC clusters only encompass a small fraction (3- 6%) of total CTC events found in the blood vasculature, they have a 25-50x higher metastatic potential and are associated with decreased overall survival in patients compared to single CTCs. Our lab discovered that CTCs produce tubulin-based protrusions, microtentacles (McTNs), which promote reattachment, retention in distant sites during metastasis and formation of tumor cell clusters. Neutrophil-CTC clusters help CTCs survive the harsh vascular environment to promote successful metastasis, however, the specific mechanism of this interaction is not fully understood. Utilizing TetherChip technology to recapitulate the nonadherent environments of metastasis, we found that primary and differentiated neutrophils produce McTNs composed of detyrosinated and acetylated α-tubulin and vimentin. Differentiation into neutrophils induced homotypic cluster formation, migration, and reattachment to fibronectin, which were all suppressed with the tubulin-depolymerizing agent, Vinorelbine. Neutrophil McTNs could also be targeted with tubulin-modulating chemotherapeutics such as Tetracaine, Paclitaxel and Cytochalasin D. Co-culturing differentiated neutrophils and tumor cells formed heterotypic clusters that enhanced migration toward multiple stimuli and Vinorelbine treatment reduced this heterotypic clustering efficiency as well as co-culture migration. Finally, differentially expressed cytokines were present in the co-culture between tumor cells and neutrophils and high expression of these signaling molecules were associated with worse prognosis in patients with breast cancer. CTC-neutrophil clusters have higher metastatic efficiency, and by demonstrating that neutrophils form McTNs, we reveal a new possible mechanism for how neutrophils interact with tumor cells. These findings further support the idea that developing cluster-disrupting therapies could provide a new targeted strategy to reduce the metastatic potential of cancer cells and yield more successful clinical outcomes.
■590 ▼aSchool code: 0373.
■650 4▼aOncology
■650 4▼aImmunology
■650 4▼aCellular biology
■653 ▼aCirculating tumor cells
■653 ▼aHeterotypic clusters
■653 ▼aMetastasis
■653 ▼aNeutrophils
■690 ▼a0992
■690 ▼a0982
■690 ▼a0379
■71020▼aUniversity of Maryland, Baltimore▼bMolecular Medicine.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0373
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358300▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
