Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma DOI Open Access
Wenjing Xuan,

Wen-Hao Hsu,

Fatima Khan

et al.

Cancer Immunology Research, Journal Year: 2022, Volume and Issue: 10(6), P. 770 - 784

Published: April 12, 2022

Abstract The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for progression. However, molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) its heterodimeric partner brain muscle ARNT-like 1 (BMAL1) glioma (GSC) drive immunosuppression GBM. Integrated analyses of data from transcriptome profiling, single-cell RNA sequencing, TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target CLOCK–BMAL1 complex GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, promotes microglial infiltration into GBM TME upregulating CD162 polarizes infiltrating microglia toward an immune-suppressive phenotype. In mouse models, inhibition CLOCK–OLFML3–HIF1α–LGMN–CD162 axis reduces intratumoral microglia, increases CD8+ T-cell infiltration, activation, cytotoxicity, synergizes anti–programmed cell death protein (anti–PD-1 therapy). human GBM, CLOCK-regulated signaling correlates positively abundance poor prognosis. Together, these findings uncover CLOCK–OLFML3–HIF1α–LGMN switch controls biology immunosuppression, thus revealing potential new therapeutic targets patients

Language: Английский

Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy DOI Creative Commons
Fatima Khan, Lizhi Pang, Madeline Dunterman

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(1)

Published: Jan. 2, 2023

Glioblastoma (GBM) is the most aggressive tumor in central nervous system and contains a highly immunosuppressive microenvironment (TME). Tumor-associated macrophages microglia (TAMs) are dominant population of immune cells GBM TME that contribute to hallmarks, including immunosuppression. The understanding TAMs has been limited by lack powerful tools characterize them. However, recent progress on single-cell technologies offers an opportunity precisely at level identify new TAM subpopulations with specific tumor-modulatory functions GBM. In this Review, we discuss heterogeneity plasticity summarize current TAM-targeted therapeutic potential We anticipate use followed functional studies will accelerate development novel effective therapeutics for patients.

Language: Английский

Citations

187
Cancer Stemness Meets Immunity: From Mechanism to Therapy DOI Creative Commons
Peiwen Chen, Wen‐Hao Hsu, Jincheng Han

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 34(1), P. 108597 - 108597

Published: Jan. 1, 2021

Cancer stem cells (CSCs) are self-renewing that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many types have revealed a prominent association between stemness immune signatures, potentially implying biological interaction such hallmark features of cancer. Emerging experimental evidence has substantiated the influence CSCs on cells, including tumor-associated macrophages, myeloid-derived suppressor T in microenvironment and, reciprocally, importance sustaining CSC its survival niche. This review covers cellular molecular mechanisms underlying symbiotic interactions how heterotypic signaling maintains tumor-promoting ecosystem informs therapeutic strategies intercepting this co-dependency.

Language: Английский

Citations

181
The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy DOI Creative Commons
Zhe Ge, Shuzhe Ding

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Nov. 3, 2020

Tumor microenvironment (TME) is composed of tumor cells and surrounding non-tumor stromal cells, mainly including associated macrophages (TAMs), endothelial carcinoma-associated fibroblasts (CAFs). The TAMs are the major components plays an important role in promoting occurrence development tumors. Macrophages originate from bone marrow hematopoietic stem embryonic yolk sacs. There close crosstalk between cells. With tumors, secrete various chemokines to recruit monocytes infiltrate tissues further promote their M2-type polarization. Importantly, M2-like can turn accelerate growth, cell invasion metastasis, inhibit immune killing progression. Therefore, targeting has become one principal strategies current immunotherapy. Current treatment focus on reducing macrophage infiltration reprogramming M1-like kill Although these treatments have had some success, effects still limited. This paper summarized recruitment polarization by support for growth research progress provide new

Language: Английский

Citations

171
Exploration and functionalization of M1-macrophage extracellular vesicles for effective accumulation in glioblastoma and strong synergistic therapeutic effects DOI Creative Commons
Xiaojun Wang, Hui Ding, Zongyang Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 16, 2022

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an extremely low survival rate. New and effective approaches for treatment are therefore urgently needed. Here, we successfully developed M1-like macrophage-derived extracellular vesicles (M1EVs) that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens GBM patients: enrichment of M2 macrophages GBM; origination majority infiltrating macrophage peripheral blood. To maximize the synergistic effect, further functionalized membranes M1EVs hydrophobic agents (the chemical excitation source CPPO (C) photosensitizer Ce6 (C)) loaded hydrophilic hypoxia-activated prodrug AQ4N (A) into inner core M1EVs. After intravenous injection, inherent nature M1-derived CCA-M1EVs allowed blood-brain barrier penetration, modulated immunosuppressive microenvironment M2-to-M1 polarization, which increased hydrogen peroxide (H2O2) levels. Furthermore, reaction between H2O2 produced energy, could be used activation to generate large amounts reactive oxygen species achieve chemiexcited photodynamic therapy (CDT). As this consumed oxygen, aggravation hypoxia also led conversion non-toxic toxic AQ4 chemotherapy. Therefore, achieved immunomodulation, CDT, chemotherapy exert potent therapeutic effect. Finally, demonstrated excellent effect against cell-derived xenograft patient-derived models, underscoring strong potential our flexible system support multi-modal therapies difficult-to-treat GBM.

Language: Английский

Citations

95
Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity DOI
Ryan C. Gimple, Kailin Yang,

Matthew Halbert

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(9), P. 497 - 514

Published: June 16, 2022

Language: Английский

Citations

87
Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle DOI Creative Commons
Meng Qu, Guoxin Zhang, Han Qu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(2)

Published: Jan. 3, 2023

Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that circadian clock controls physiological homeostasis of liver and plays key role in hepatocarcinogenesis. Despite progress, cellular molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing knowledge gap, we show here although human HCC cells Hep3B, HepG2, Huh7 displayed variations rhythm profiles, all relied on master transcription factors, BMAL1 CLOCK, for sustained cell growth. Down-regulating Bmal1 or Clock induced apoptosis arrested cycle at G 2 /M phase. Mechanistically, found inhibiting / dysregulation regulators Wee1 p21 which cooperatively contribute to tumor death. knockdown caused downregulation led activation upregulation Collectively, our results suggest CLOCK promote proliferation by controlling levels, thereby preventing arrest. Our findings shed light impact proteins maintaining oncogenesis provide proof-of-principle developing cancer therapy based modulation clock.

Language: Английский

Citations

79
Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives DOI Creative Commons

Hao Lin,

Chaxian Liu,

An-Kang Hu

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 8, 2024

Abstract Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, exploration of emerging modalities such as immunotherapy integration medicine engineering technology therapy, efficacy these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny inhibitory milieu within GBM has underscored significance cellular constituents microenvironment their interactions with cells neurons. Novel immune targeted therapy strategies have emerged, offering promising avenues for advancing treatment. One pivotal mechanism orchestrating immunosuppression involves aggregation myeloid-derived suppressor (MDSCs), glioma-associated macrophage/microglia (GAM), regulatory T (Tregs). Among these, MDSCs, though constituting minority (4–8%) CD45 + GBM, play central component fostering evasion propelling tumor progression, angiogenesis, invasion, metastasis. MDSCs deploy intricate mechanisms that adapt dynamic (TME). Understanding interplay between provides compelling basis This review seeks elucidate inherent explore existing targets, consolidate insights into MDSC induction contribution immunosuppression. Additionally, comprehensively surveys ongoing clinical trials potential strategies, envisioning future where targeting could reshape landscape GBM. Through synergistic other modalities, this approach can establish multidisciplinary, multi-target paradigm, ultimately improving prognosis quality life patients

Language: Английский

Citations

62
Hallmarks of cancer stemness DOI Creative Commons

Jia-Jian Loh,

Stephanie Ma

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(5), P. 617 - 639

Published: May 1, 2024

Language: Английский

Citations

60
Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma DOI Creative Commons
Lizhi Pang, Madeline Dunterman, Wenjing Xuan

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112127 - 112127

Published: Feb. 1, 2023

Glioblastoma (GBM) is one of the most aggressive tumors in adult central nervous system. We previously revealed that circadian regulation glioma stem cells (GSCs) affects GBM hallmarks immunosuppression and GSC maintenance a paracrine autocrine manner. Here, we expand mechanism involved angiogenesis, another critical hallmark, as potential basis underlying CLOCK's pro-tumor effect GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation periostin (POSTN). As result, secreted POSTN promotes tumor angiogenesis via activation TANK-binding kinase 1 (TBK1) signaling endothelial cells. In mouse patient-derived xenograft models, blockade POSTN-TBK1 axis inhibits progression angiogenesis. Thus, CLOCK-POSTN-TBK1 circuit coordinates key tumor-endothelial cell interaction represents an actionable therapeutic target for

Language: Английский

Citations

46
Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression DOI Creative Commons
Fatima Khan, Yiyun Lin, Heba Ali

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 5, 2024

Abstract Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs migration lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling functional studies demonstrate A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer activator transcription 3 (STAT3) transcriptional co-activators in cells to upregulate C-C motif chemokine ligand 2 (CCL2) CCL7, which recruit macrophages into microenvironment. Reciprocally, infiltrating produce LDHA-containing vesicles promote glycolysis, proliferation, survival. Genetic pharmacological inhibition LDHA-mediated tumor-macrophage symbiosis markedly suppresses progression mouse models. Analysis plasma samples patients confirms LDHA its downstream signals potential biomarkers correlating positively with density. Thus, provides therapeutic targets for

Language: Английский

Citations

39