HIF2A mediates lineage transition to aggressive phenotype of cancer-associated fibroblasts in lung cancer brain metastasis
Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associ...
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Published in | Oncoimmunology Vol. 13; no. 1; p. 2356942 |
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Abstract | Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets. |
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AbstractList | Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets. ABSTRACTBrain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets. Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets.Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets. |
Author | Fu, Minjie Mao, Ying Zhu, Xianmin Zhuang, Zhengping Zhang, Licheng Hua, Wei Shen, Zhewei You, Muyuan Feng, Yuan |
Author_xml | – sequence: 1 givenname: Muyuan surname: You fullname: You, Muyuan organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 2 givenname: Minjie surname: Fu fullname: Fu, Minjie organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 3 givenname: Zhewei surname: Shen fullname: Shen, Zhewei organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 4 givenname: Yuan surname: Feng fullname: Feng, Yuan organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 5 givenname: Licheng surname: Zhang fullname: Zhang, Licheng organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 6 givenname: Xianmin surname: Zhu fullname: Zhu, Xianmin organization: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China – sequence: 7 givenname: Zhengping surname: Zhuang fullname: Zhuang, Zhengping organization: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA – sequence: 8 givenname: Ying surname: Mao fullname: Mao, Ying organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China – sequence: 9 givenname: Wei surname: Hua fullname: Hua, Wei organization: Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China |
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Keywords | lung cancer tumor microenvironment HIF Brain metastasis Cancer-Associated Fibroblasts |
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Snippet | Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung... ABSTRACTBrain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME)... |
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SubjectTerms | Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Brain metastasis Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - secondary Cancer-Associated Fibroblasts Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Cell Line, Tumor Cell Lineage Gene Expression Regulation, Neoplastic HIF Humans lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Lung Neoplasms - secondary Mice Neovascularization, Pathologic - genetics Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Original Research Phenotype Single-Cell Analysis Tumor Microenvironment |
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Title | HIF2A mediates lineage transition to aggressive phenotype of cancer-associated fibroblasts in lung cancer brain metastasis |
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