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Moving Beyond M1/M2: Xenoline-Polarized Macrophages as a Physiologically Relevant Model of Tumor-Associated Macrophages in Glioblastoma
Moving Beyond M1/M2: Xenoline-Polarized Macrophages as a Physiologically Relevant Model of Tumor-Associated Macrophages in Glioblastoma
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104641
- ISBN
- 9798293828937
- DDC
- 616.079
- 저자명
- Alrefai, Hasan.
- 서명/저자
- Moving Beyond M1/M2: Xenoline-Polarized Macrophages as a Physiologically Relevant Model of Tumor-Associated Macrophages in Glioblastoma
- 발행사항
- [Sl] : The University of Alabama at Birmingham, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 256 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Willey, Christopher D.;Miller, C. Ryan.
- 학위논문주기
- Thesis (Ph.D.)--The University of Alabama at Birmingham, 2025.
- 초록/해제
- 요약Glioblastoma (GBM) remains one of the most treatment-refractory cancers, with few therapeutic advances translating into survival benefit. With a median survival of just 15-18 months, the need for effective therapies is urgent. A key obstacle is the underutilization of tumor-associated macrophages (TAMs) in preclinical models. TAMs account for a sizable proportion of GBM by mass and drive malignant behaviors such as angiogenesis, invasion, and resistance to chemoradiotherapy, making them attractive therapeutic targets. Unfortunately, most in vitro GBM-TAM models are inadequate, as they fail to capture the cellular heterogeneity and microenvironmental interactions that drive tumor progression, therapeutic resistance, and immune evasion.To address this gap, we developed and rigorously characterized a fully serum-free triculture platform of GBM patient-derived xenograft (PDX) cell lines, astrocytes, and macrophages. This system preserves the stem-like properties of PDX cells while supporting canonical astrocyte and macrophage functions. When cultured together, GBM PDX cells upregulate markers of hypoxia and stemness, underscoring the importance of including non-neoplastic stromal cells to recreate a physiologically relevant model system in vitro.Furthermore, we demonstrated that these GBM PDX cells polarize our macrophages to a unique TAM-like state that diverges from the classical M1/M2 polarization states that are frequently used to model TAM interactions. We also demonstrated that macrophages polarized by RT-selected GBM PDX cells exhibit a phenotype characterized by elevated interferon signatures, which we validated using spatial transcriptomics on 10 matched primary and recurrent GBM samples. Our model offers a scalable in vitro system faithfully recapitulates GBM-TAM crosstalk, thereby allowing us to study the effects of genetically distinct GBMs on TAM polarization.Preliminary spatial analysis of human GBM samples revealed niche-specific enrichment of macrophage subtypes. Lipid-catabolic macrophage signatures were enriched in the invasive edge, the region responsible for post-resection recurrence, while inflammatory and phagocytic macrophage signatures were enriched in the hypoxic core. Confirming these spatial patterns in situ will benchmark further refinement of our triculture model system. Altogether, this dissertation presents a high-throughput, physiologically faithful in vitro model of GBM-TAM interactions that is poised to accelerate immunomodulatory drug discovery and deepen our understanding of tumor-immune crosstalk in GBM.
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 키워드
- Glioblastoma
- 기타저자
- The University of Alabama at Birmingham Health Professions
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798293828937
■035 ▼a(MiAaPQ)AAI32114020
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aAlrefai, Hasan.
■24510▼aMoving Beyond M1/M2: Xenoline-Polarized Macrophages as a Physiologically Relevant Model of Tumor-Associated Macrophages in Glioblastoma
■260 ▼a[Sl]▼bThe University of Alabama at Birmingham▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a256 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Willey, Christopher D.;Miller, C. Ryan.
■5021 ▼aThesis (Ph.D.)--The University of Alabama at Birmingham, 2025.
■520 ▼aGlioblastoma (GBM) remains one of the most treatment-refractory cancers, with few therapeutic advances translating into survival benefit. With a median survival of just 15-18 months, the need for effective therapies is urgent. A key obstacle is the underutilization of tumor-associated macrophages (TAMs) in preclinical models. TAMs account for a sizable proportion of GBM by mass and drive malignant behaviors such as angiogenesis, invasion, and resistance to chemoradiotherapy, making them attractive therapeutic targets. Unfortunately, most in vitro GBM-TAM models are inadequate, as they fail to capture the cellular heterogeneity and microenvironmental interactions that drive tumor progression, therapeutic resistance, and immune evasion.To address this gap, we developed and rigorously characterized a fully serum-free triculture platform of GBM patient-derived xenograft (PDX) cell lines, astrocytes, and macrophages. This system preserves the stem-like properties of PDX cells while supporting canonical astrocyte and macrophage functions. When cultured together, GBM PDX cells upregulate markers of hypoxia and stemness, underscoring the importance of including non-neoplastic stromal cells to recreate a physiologically relevant model system in vitro.Furthermore, we demonstrated that these GBM PDX cells polarize our macrophages to a unique TAM-like state that diverges from the classical M1/M2 polarization states that are frequently used to model TAM interactions. We also demonstrated that macrophages polarized by RT-selected GBM PDX cells exhibit a phenotype characterized by elevated interferon signatures, which we validated using spatial transcriptomics on 10 matched primary and recurrent GBM samples. Our model offers a scalable in vitro system faithfully recapitulates GBM-TAM crosstalk, thereby allowing us to study the effects of genetically distinct GBMs on TAM polarization.Preliminary spatial analysis of human GBM samples revealed niche-specific enrichment of macrophage subtypes. Lipid-catabolic macrophage signatures were enriched in the invasive edge, the region responsible for post-resection recurrence, while inflammatory and phagocytic macrophage signatures were enriched in the hypoxic core. Confirming these spatial patterns in situ will benchmark further refinement of our triculture model system. Altogether, this dissertation presents a high-throughput, physiologically faithful in vitro model of GBM-TAM interactions that is poised to accelerate immunomodulatory drug discovery and deepen our understanding of tumor-immune crosstalk in GBM.
■590 ▼aSchool code: 0005.
■650 4▼aImmunology
■650 4▼aCellular biology
■650 4▼aMolecular biology
■653 ▼aGlioblastoma
■653 ▼aTumor-associated macrophages
■653 ▼aPatient-derived xenograft
■653 ▼aDrive tumor progression
■690 ▼a0982
■690 ▼a0379
■690 ▼a0307
■71020▼aThe University of Alabama at Birmingham▼bHealth Professions.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0005
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358305▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
