Tumor cells modulate macrophage phenotype in a novel in vitro co-culture model of the non-small cell lung cancer tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA825550 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18717612_1.fastq.gz | Fastqsanger.gz | |||
| SRR18717612_2.fastq.gz | Fastqsanger.gz | |||
| SRR18717613_1.fastq.gz | Fastqsanger.gz | |||
| SRR18717613_2.fastq.gz | Fastqsanger.gz | |||
| SRR18717614_1.fastq.gz | Fastqsanger.gz |
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Project description:Introduction: Macrophage phenotype in the tumor microenvironment correlates with prognosis in non-small cell lung cancer (NSCLC). Immunosuppressive macrophages promote tumor progression, while pro-inflammatory macrophages may drive an anti-tumor immune response. How individual NSCLCs impact macrophage phenotype is a major knowledge gap. Methods: To systematically study the impact of lung cancer cells on macrophage phenotypes, we developed an in vitro co-culture model comprised of molecularly and clinically-annotated patient-derived NSCLC lines, human cancer-associated fibroblasts, and murine macrophages. Induced macrophage phenotype was studied through qRT-PCR and validated in vivo using NSCLC xenografts through quantitative immunohistochemistry and clinically with TCGA “matched” patient tumors. Results: 72 NSCLC cell lines were studied. The most frequent highly induced macrophage-related gene was Arginase-1, reflecting an immunosuppressive M2-like phenotype. This was independent of multiple clinicopathologic factors, which also did not impact M2:M1 ratios in matched TCGA samples. In vivo, tumors established from high Arginase-1-inducing lines (Arghi) had a significantly elevated density of Arg1+ macrophages. Matched TCGA clinical samples to Arghi NSCLC lines had a significantly higher ratio of M2:M1 macrophages. Conclusions: In our preclinical model, a large panel of patient-derived NSCLC lines most frequently induced high expression Arginase-1 in co-cultured mouse macrophages, independent of major clinicopathologic and oncogenotype-related factors. Arghi cluster-matched TCGA tumors contained a higher ratio of M2:M1 macrophages. Thus, this preclinical model reproducibly characterizes how individual NSCLCs modulate macrophage phenotype, correlates with macrophage polarization in clinical samples, and can serve as an accessible platform for further investigation of macrophage-specific therapeutic strategies.
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Project description:IntroductionMacrophage phenotype in the tumor microenvironment correlates with prognosis in NSCLC. Immunosuppressive macrophages promote tumor progression, whereas proinflammatory macrophages may drive an antitumor immune response. How individual NSCLCs affect macrophage phenotype is a major knowledge gap.MethodsTo systematically study the impact of lung cancer cells on macrophage phenotypes, we developed an in vitro co-culture model that consisted of molecularly and clinically annotated patient-derived NSCLC lines, human cancer-associated fibroblasts, and murine macrophages. Induced macrophage phenotype was studied through quantitative real-time polymerase chain reaction and validated in vivo using NSCLC xenografts through quantitative immunohistochemistry and clinically with The Cancer Genome Atlas (TCGA)-"matched" patient tumors.ResultsA total of 72 NSCLC cell lines were studied. The most frequent highly induced macrophage-related gene was Arginase-1, reflecting an immunosuppressive M2-like phenotype. This was independent of multiple clinicopathologic factors, which also did not affect M2:M1 ratios in matched TCGA samples. In vivo, xenograft tumors established from high Arginase-1-inducing lines (Arghi) had a significantly elevated density of Arg1+ macrophages. Matched TCGA clinical samples to Arghi NSCLC lines had a significantly higher ratio of M2:M1 macrophages (p = 0.0361).ConclusionsIn our in vitro co-culture model, a large panel of patient-derived NSCLC lines most frequently induced high-expression Arginase-1 in co-cultured mouse macrophages, independent of major clinicopathologic and oncogenotype-related factors. Arghi cluster-matched TCGA tumors contained a higher ratio of M2:M1 macrophages. Thus, this in vitro model reproducibly characterizes how individual NSCLC modulates macrophage phenotype, correlates with macrophage polarization in clinical samples, and can serve as an accessible platform for further investigation of macrophage-specific therapeutic strategies.
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Project description:Molecular mechanisms of the cancer cells-macrophages interactions growing in vitro conditions as a co-culture. The five canine mammary cancer cell lines were cultured with monocytes sorted from the canine blood for 72hrs. Then, the cancer cells and macrophages were sorted and the gene expression analysis was conducted. The control for each co-cultured cell line was the same cell line growing as a single culture, whereas the control for the macrophages growing in a co-culture conditions were macrophages growing as a single culture. Solid tumors are comprised of various cells, like cancer cells, resident stromal cells, migratory hemopoietic cells and so on. These cells regulate tumor growth and metastasis. Macrophages are probably the most important element of the interactions within the tumor microenvironment. However, the molecular mechanism how the tumor environment can educate tumor-associated macrophages (TAMs) toward a tumor-promoting phenotype still remains unknown. Moreover, there are no information how the presence of macrophages change the cancer cells phenotype. Exploring the underlying molecular mechanisms of these phenomena was the aim of this study. Solid tumors are comprised of various cells, like cancer cells, resident stromal cells, migratory hemopoietic cells and so on. These cells regulate tumor growth and metastasis. Macrophages are probably the most important element of the interactions within the tumor microenvironment. However, the molecular mechanism how the tumor environment can educate tumor-associated macrophages (TAMs) toward a tumor-promoting phenotype still remains unknown. Moreover, there are no information how the presence of macrophages change the cancer cells phenotype. Exploring the underlying molecular mechanisms of these phenomena was the aim of this study. Dye-swap experiment, each cell line growing in the co-culture conditions was compared to the same cell line growing as a single culture, macrophages growing in the co-culture conditions were compared to the macrophages growing as the single culture.
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