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Lung epithelial transcriptional responses to bleomycin and effects of IRE1α or TGFβ inhibition

ABSTRACT: Lung epithelial transcriptional responses to bleomycin and effects of IRE1α or TGFβ inhibition

PROVIDER: PRJNA788524 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17228500.fastq.gz	Fastqsanger.gz
	SRR17228501.fastq.gz	Fastqsanger.gz
	SRR17228502.fastq.gz	Fastqsanger.gz
	SRR17228503.fastq.gz	Fastqsanger.gz
	SRR17228504.fastq.gz	Fastqsanger.gz

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Lung epithelial transcriptional responses to bleomycin and effects of IRE1α or TGFβ inhibition

Project description:This experiment sought to characterize the epithelial-specific transcriptional response in the bleomycin model of lung fibrosis, and the contribution of IRE1a and the TGFb-activating integrin avb6 to this response. "Ribotag" mice were crossed to ShhCre mice, both on the C57BL/6 background to generate experimental cohorts. Mice used for the experiment conditionally expressed HA-tagged ribosomal protein Rpl22 in the epithelium. Mice were exposed to intranasal bleomycin (3 U/kg) on day 1 and subsequently treated with the IRE1a kinase inhibitor KIRA8 (50 mg/kg daily), or the anti-integrin beta6 antibody 3G9 (10 mg/kg on day 1 and day 4). Treatment controls were either drug vehicle (3% ethanol, 7% Tween80, and 90% saline) or the inert antibody Axum8 in saline). Lungs were harvested on day 7 after bleomycin exposure, flash-frozen, and later homogenized under native conditions with cycloheximide. An aliquot of the “input” homogenate was removed and total RNA purified by Qiagen RNeasy Mini and is representative of the whole-lung transcriptome/translatome. The remaining homogenate was subjected to immunoprecipitation of HA-tagged polysomes, followed by RNA purification by Qiagen RNeasy Micro, and is representative of the lung epithelial transcriptome/translatome.

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Single-cell sequencing of mouse lung epithelial cells after bleomycin injury and modulation of IRE1α

Project description:Epithelial cells that are committed to a differentiated state in homeostasis can change their identity in response to injury. In the lung, alveolar type 2 (AT2) cells are the resident secretory epithelial cells of the alveolus, and after injury can proliferate and differentiate into type 1 cells. This inducible plasticity is central to alveolar regeneration, fibrosis, and malignancy, but the regulatory pathways that govern the balance between fate maintenance and differentiation are incompletely understood. Epithelial cells that are committed to a differentiated state in homeostasis can change their identity in response to injury. In the lung, alveolar type 2 (AT2) cells are the resident secretory epithelial cells of the alveolus, and after injury can proliferate and differentiate into type 1 cells. This inducible plasticity is central to alveolar regeneration, fibrosis, and malignancy, but the regulatory pathways that govern the balance between fate maintenance and differentiation are incompletely understood. IRE1α is an ER transmembrane protein conserved throughout eukaryotes that senses misfolded protein in the ER lumen and initiates cellular efforts to regain protein folding homeostasis through its cytosolic kinase and RNase domains. We previously showed that IRE1α pharmacologic or genetic loss of function decreased the accumulation of damage-associated transient progenitors (DATPs), and also promoted their differentiation into new alveolar epithelial cells. To further detail the functions of IRE1α after AT2 injury, we performed single-cell transcriptome profiling of the AT2-to-AT1 transition after bleomycin injury, with pharmacologic or epithelial-specific genetic loss of IRE1α function.

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Single-cell sequencing of mouse lung epithelial cells after bleomycin injury and modulation of IRE1α

Project description:Single-cell sequencing of mouse lung epithelial cells after bleomycin injury and modulation of IRE1α

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INS1 cells expressing either WT IRE1α, I642G IRE1α, N906A IRE1α, or spliced XBP1 treated with dox and 1NMPP1

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Project description:Ewing sarcoma is an aggressive cancer most commonly diagnosed in adolescents and young adults. Various mechanisms of TGFβ inhibition are being tested in clinical trials for patients with relapsed Ewing sarcoma. However, the functional impact of TGFβ inhibition on the Ewing tumor microenvironment remains largely unstudied given the historical lack of immunocompetent preclinical models of Ewing sarcoma. Here, we use single cell RNAseq analysis of human Ewing tumors to demonstrate that immune cells are the largest source of TGFβ production in the human Ewing tumor microenvironment. We develop and utilize a humanized mouse model of Ewing sarcoma to study the effect of TGFβ inhibition on the Ewing tumor immune microenvironment both at baseline and during radiation therapy, a treatment that enhances TGFβ activation and is often used to treat patients with aggressive Ewing sarcoma. Finally, we utilize a bivalent ligand TGFβ TRAP and demonstrate that, in combination with radiation, TGFβ inhibition both increases immune cell infiltration in Ewing tumors and decreases lung metastatic burden.

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Whole transcriptome analysis of control human fibroblasts, TGFβ-induced human fibroblasts, and fibroblasts co-cultured with normal lung decellularized scaffolds and fibroblasts co-cultured with bleomycin-induced lung decellularized scaffolds.

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Project description:Only 13% of newly diagnosed pancreatic cancer cases are surgically resectable, emphasizing the importance of systemic therapy. Yet, the 5-year overall survival rate for pancreatic cancer remains ~13%, underscoring the urgent need for new treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristic of pancreatic cancer. Over 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none have gained FDA approval. Nevertheless, TGFβ blockade may hold promise for a subset of cancers with non-functional TGFβ signaling. Greater than 25% of pancreatic cancers carry mutations in SMAD4, a key component of canonical TGFβ signaling. In this study, we investigate the potential for stratifying patients based on SMAD4 mutational status to identify tumors susceptible to TGFβ inhibition. Analysis of SMAD4 expression in human pancreatic tumors reveals that SMAD4 mutation or loss is associated with worse disease-free survival. Intriguingly, we observe heterogeneity in intratumoral SMAD4 expression among human pancreatic cancer samples. To investigate the consequences of SMAD4 mutation, we employed SMAD4-deficient genetically engineered mouse models and orthotopic SMAD4 knockout models, which exhibited reduced survival, increased metastasis, and alterations in the tumor microenvironment compared to SMAD4 wildtype controls, consistent with gene and protein expression changes in the absence of functional SMAD4. Importantly, mice bearing SMAD4-deficient tumors treated with a blocking TGFβ antibody exhibited reduced tumor weight and improved survival. These findings suggest that targeting TGFβ signaling in TGFβ-deficient tumors has potential utility in pancreatic cancer.

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