IL13Rα2 promotes the proliferative switch required for outgrowth of breast cancer brain metastases
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA698556 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13600501.fastq.gz | Fastqsanger.gz | |||
| SRR13600502.fastq.gz | Fastqsanger.gz | |||
| SRR13600503.fastq.gz | Fastqsanger.gz | |||
| SRR13600504.fastq.gz | Fastqsanger.gz | |||
| SRR13600505.fastq.gz | Fastqsanger.gz |
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Project description:The survival of women with brain metastases (BM) from breast cancer remains very poor, and more than 80% will die within a year of their diagnosis. Here we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) in vitro and in vivo, and postulate IL13Rα2 as a suitable therapeutic target for BM. Experimental design: We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value. Using inducible-shRNAs in TNBC and HER2+ breast-brain metastatic models we assessed IL13Rα2 function in vitro and in vivo. We performed RNAseq and functional studies to define the molecular mechanisms underlying IL13Rα2 function in BCBM. Results: High IL13Rα2 expression in BCBM predicted worse survival after BM diagnoses. IL13Rα2 was essential for cancer-cell survival, promoting proliferation while repressing invasion. IL13Rα2 KD resulted in repression of cell cycle and proliferation mediator Cyclin D2 and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells in vitro, (ii) marked micrometastasis and invasive fronts in BCBM, (iii) predicted shorter disease-free survival (DFS) and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 prior or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and a switch to a more proliferative phenotype is critical to BM outgrowth.
2021-06-30 | GSE165898 | GEO
Project description:Platelets favor the outgrowth of established metastases
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Project description:Despite abundant evidence demonstrating that platelets foster metastasis, anti- platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.
2024-03-10 | E-MTAB-13864 | biostudies-arrayexpress
Project description:When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis, and alveolar epithelial cells are the most common cell type in the lung. A gap in our ability to treat patients with established lung metastases lies in our lack of knowledge regarding how the lung microenvironment is remodeled during metastatic outgrowth and how this contributes to disease progression. Immunocompetent preclinical mouse models of BC metastasis were used to study late-stage lung metastatic outgrowth, the stage at which most patients are diagnosed with metastatic disease. A custom imaging panel was developed to quantify lung wound repair and inflammation, and single-cell RNA-sequencing (scRNAseq) was performed on mouse lungs with high or low metastatic burden to identify cell-type specific genes altered during metastatic outgrowth. No-contact co-culture experiments were used to examine reciprocal paracrine interactions between lung type II alveolar epithelial (AT2) cells and BC cells. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth, which was characterized by an increased number and activation of AT2 cells surrounding growing metastases. scRNAseq of lungs with a high versus low metastatic burden showed that metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. No-contact co-culture experiments indicated that BC-derived secreted factors alter AT2 gene expression, while AT2-derived secreted factors promoted TNBC growth. We investigated the possible mechanism(s) responsible for these effects and found that AT2 secreted factor genes, regulated by the cAMP response element-binding protein (CREB), contribute to BC proliferation. Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation with PDE4 inhibitors. This strategy may be an effective way to treat and manage metastatic BC progression in established, clinically detectable disease.
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Project description:Combining RNA sequencing of breast cancer brain metastases with reverse genetic screen in Drosophila melanogaster, we identified Rab11b, an endosomal recycling protein, as a mediator of metastatic adaptation. We show that disseminated cells up-regulate Rab11b early after arrival in the brain, allowing control of the cell surface proteome through recycling of proteins required for successful interaction with the microenvironment, including integrin B1. Rab11b-mediated control of integrin B1 surface expression allows ligation to the brain ECM, activating mechanotransduction signaling to allow survival and proliferation. We propose a model in which up-regulation of Rab11b allows disseminated cells to recycle needed proteins during metastatic adaptation, without strictly requiring transcription and translation, to allow for metastatic outgrowth.
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Project description:Cancer stem cells (CSCs) are a minority population of cancer cells that display stem cell-like multipotent and self-renewal properties. They give rise to the bulk of cancer cells with limited replicative potential. In colorectal cancer (CRC), CSCs are marked by expression of the leucine-rich repeat-containing G-protein receptor 5 (Lgr5). Since CSCs display multipotent and self-renewal properties, this population is thought to seed metastases. Here, we used a mouse model and human xenografts to investigate the cell-of-origin of metastases. Surprisingly, we found that most CRC cells that disseminated and entered the blood circulation were Lgr5-. Lgr5- cancer cells arriving at the metastatic site formed lesions in which Lgr5+ CSCs appeared. This plasticity could occur independently of stemness-inducing factors, and was an indispensable event for the outgrowth of metastases, since neutralization of this plasticity prevented metastatic outgrowth. Combined, our study shows that most metastases are seeded by Lgr5- cancer cells, and that these cells have a niche-independent and intrinsic capacity to become CSCs and restore epithelial hierarchy.
2020-03-18 | GSE143988 | GEO
Project description:When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth in immunocompetent preclinical mouse models of BC. This phenotype was characterized by an increased number and activation of lung type II alveolar epithelial (AT2) cells surrounding growing metastases. Metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. AT2-derived secreted factors also promote triple-negative breast cancer (TNBC) growth. AT2 secreted factors are regulated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. Finally, AT2 cells adjacent to metastases in lungs from patients with metastatic BC express higher PDE4B compared to AT2 cells in normal lungs. Alveolar epithelial cells are the most common cell type in the lung. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation during metastatic outgrowth with FDA-approved PDE4 inhibitors. This strategy may be an effective way to treat and manage progression of established metastatic BC within the lung.
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