β-Catenin signaling in alveolar macrophages enhances lung metastasis through a TNF-dependent mechanism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA824851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18687412_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687412_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687413_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687413_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687414_1.fastq.gz | Fastqsanger.gz |
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Project description:The main cause of malignancy-related mortality is metastasis. While metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment (TME), especially macrophages. Recruited macrophages infiltrating the TME are correlated with worse outcomes, because they are rendered pro-tumorigenic through defined tumor-driven transcription factor-mediated programs. However, the pathways that govern the dysregulation of tissue-resident macrophages (TRMs) are less well understood. Alveolar macrophages (AMs) are a TRM population with critical roles in both tissue homeostasis and metastasis. Wnt/β-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that β-catenin expression in AMs enhances metastasis in solid tumor models. Using a novel genetic β-catenin gain-of-function approach, we demonstrated that 1) enhanced β-catenin in AMs heightened lung metastasis; 2) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and 3) localized TNF blockade abrogated this metastatic outcome. Lastly, CTNNB1 and TNF expression were positively correlated in AMs of lung cancer patients. Overall, our findings revealed a novel Wnt/β-catenin–TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to TNF-α induced necrosis.
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Project description:The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow-derived and tissue-resident populations. In contrast to bone marrow-derived macrophages, the transcriptional pathways that govern the pro-metastatic activities of tissue-resident macrophages (TRMs) remain less clear. Alveolar macrophages (AMs) are a TRM population with critical roles in tissue homeostasis and metastasis. Wnt/β-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that β-catenin expression in AMs enhances metastasis in solid tumor models. Using a genetic β-catenin gain-of-function approach, we demonstrated that (a) enhanced β-catenin in AMs heightened lung metastasis; (b) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and (c) localized TNF-α blockade abrogated this metastatic outcome. Last, β-catenin gene CTNNB1 and TNF expression levels were positively correlated in AMs of patients with lung cancer. Overall, our findings revealed a Wnt/β-catenin/TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to the antineoplastic actions of TNF-α.
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Project description:It is well-recognized that macrophages, which arise from circulating precursors, enhance tumor progression in patients and animal models. However, less is known regarding the role of tissue-resident macrophages in metastasis. Moreover, the identification of tumor factors which influence macrophage function in the metastatic niche remains incomplete. Here, we investigated one such cytokine known as thymic stromal lymphopoietin (TSLP). Our rationale to focus on TSLP was based on two non-overlapping findings; first, TSLP exacerbates asthma in part by altering the lung macrophage response and, secondly, TSLP is produced by certain mouse and human tumor systems, although its role in neoplasia remains understudied. Thus, we tested the hypothesis that tumor-derived TSLP augments lung metastasis by rendering alveolar macrophages pro-tumorigenic. To test this hypothesis, we principally employed the 4T1 tumor model, which produces high levels of TSLP and metastasizes to the lung. TSLP loss-of-function significantly reduced spontaneous lung metastasis, as well as lung colonization. Moreover, similar outcomes were observed in both wild-type and immune-deficient hosts, suggesting that TSLP acted on innate immune cells such as macrophages. To test this notion, pharmacologic depletion of alveolar macrophages significantly reduced lung tumor growth of the TSLP-expressing, but not TSLP-deficient tumor population. In contrast, depleting macrophages originating from the circulation did not impact lung tumor growth. Lastly, TSLP increased the invasive and angiogenic gene expression profile of the alveolar macrophage population. Altogether, our study identified a novel TSLP-alveolar macrophage axis in lung metastasis, which offers new insights into mechanisms of metastasis and potential therapeutic targets.
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