β-Catenin signaling in alveolar macrophages enhances lung metastasis through a TNF-dependent mechanism
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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:Transcriptional Profiling of Human Alveolar Epithelial Cells stimulated with TNF-alpha
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Project description:Alveolar hemorrhage (AH) is a life-threatening condition with a high mortality rate, of immune cells in its pathogenesis remains poorly defined. Here, we report of β-catenin stabilization under Lck promoter and its impact on yet the role the protective function AH. Using a novel transgenic mouse model (CAT-Tg) with stabilized β-catenin, we demonstrate that β-catenin stabilization induces a distinct T-cell phenotype characterized by an expansion of central effector memory cells (CD44⁺, CD122⁺, Eomes⁺, T-bet⁺). Mechanistically, this effect was associated with suppression of key proinflammatory pathways, including reduced phosphorylation of STAT1, STAT3, and JAK1. AH was induced using pristane, and CAT-Tg mice were significantly protected from lung damage, showing reduced proteinuria and decreased pulmonary proinflammatory cytokine production compared with wild-type (WT). This protection correlated with a marked increase in FOXP3⁺ regulatory T cells (Tregs) in CAT-Tg mice. We further identified a novel mechanism in which β-catenin stabilization enhances lung expression of Amphiregulin and BATF, two molecules essential for Treg function and tissue repair. Adoptive transfer of Tregs from CAT-Tg mice into WT mice with pristane-induced AH conferred superior protection, as evidenced by reduced lung inflammation and proteinuria. The systemic administration of a β-catenin agonist to mice with AH significantly attenuated disease severity. Our bioinformatic analysis confirmed that β-catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings reveal that β-catenin stabilization protects against alveolar hemorrhage by inducing a specialized T-cell phenotype and establishing a protective Amphiregulin–BATF–Treg axis. This study identifies a novel immunomodulatory pathway with therapeutic potential for AH and other inflammatory lung diseases.
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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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Project description:Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes - highly metastatic (HM) and non-metastatic (NM) - both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases although it was equally tumorigenic. Using comparative label-free quantitative LC-MS/MS, we identified b-catenin which we demonstrated for the first time a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of b-catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the microRNA processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to-mesenchymal transition and subsequent stem cell traits. Silencing b-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. B-catenin knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover b-catenin as a critical player in promoting ovarian cancer aggressiveness and a new mechanism linking between b-catenin and miRNA downregulation underlying this process.
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Project description:Introduction: A growing body of literature suggests a role for neuroinflammation in retinal ganglion cell (RGC) death in glaucoma. For instance, deficiency of three proinflammatory cytokines, complement component 1, subcomponent q (C1q), interleukin 1 alpha (Il1a), and tumor necrosis factor (Tnf), resulted in significant protection of RGCs after glaucoma-relevant insults. While TNF and C1Q have been extensively investigated in glaucoma-relevant model systems, the role of IL1A in RGCs is not well defined. Methods: Eyes of 2-4 month-old C57BL/6J mice or mice deficient in either Jun or Sarm1 were intravitreally injected with IL1A alone, TNF alone, or IL1A and TNF together. Retinal flat mounts were assessed for RGC survival using immunostaining of RBPMS. Bulk RNA-sequencing and differential expression analyses of retinal tissue was performed to determine molecular changes in response to IL1A, TNF, and IL1A combined with TNF within C57BL/6J and Sarm1 deficient mice. Results: Intravitreal injection of IL1A did not result in RGC death at either 14 days or 12 weeks. Consistent with previous studies, TNF injection did not cause significant RGC loss at 14 days but did after 12 weeks. Together, IL1A+TNF resulted in a relatively rapid RGC death, driving significant loss two weeks after injection. We identified molecular changes which occur in response to IL1A and to combined IL1A+TNF treatment with limited changes identified in TNF alone treated eyes. Using mice deficient in Jun or Sarm1, we showed RGC loss after IL1A+TNF insult is JUN-independent and SARM1-dependent. Furthermore, RNA-seq analysis showed Sarm1 deficiency does not stop the neuroinflammatory response to IL1A+TNF. Discussion: We identified a novel role of IL1A, we found that IL1A acted as a sensitizer to TNF-induced death. Co-injection of IL1A and TNF resulted in rapid RGC death, with significant RGC loss 14 days after injection. TNF+IL1A-induced RGC death did not depend on JUN activation and was rather SARM1 dependent. Also, RNA-seq analyses indicated that while Sarm1 deficiency protected from IL1A+TNF induced RGC loss it did not significantly alter microglia and astrocyte responses. Altogether, these findings indicate that IL1A potentiates SARM1-dependent TNF-induced RGC death in vivo.
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