P140Cap overexpression in Balb-neuT HER2 breast cancer transgenic mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA735525 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14743538.fastq.gz | Fastqsanger.gz | |||
| SRR14743539.fastq.gz | Fastqsanger.gz | |||
| SRR14743540.fastq.gz | Fastqsanger.gz | |||
| SRR14743541.fastq.gz | Fastqsanger.gz | |||
| SRR14743542.fastq.gz | Fastqsanger.gz |
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Project description:In HER2-positive breast cancer patients the adaptor protein p140Cap correlates with increased patient survival and decreased probability to develop metastasis. Causally, p140Cap negatively regulates in vitro and in vivo breast tumor properties. Here we show that p140Cap status correlates with a rewiring of the tumor immune microenvironment, with an increased presence of tumor-infiltrating lymphocytes (TILs) in human breast cancers and an inverse correlation with inflammatory hallmarks. Preclinical syngeneic p140Cap models show a significant increase of CD8+ T-Lymphocytes, NK cells and M1-macrophages in p140Cap tumors, a reduced mobilization and a decreased recruitment of G-CSF-dependent Myeloid-Derived Suppressor Cells (MDSC), with a specific reduction in G-CSF mRNA and protein levels. Indeed, p140Cap impacts on the G-CSF axis by reducing the fraction of Tumour-Initiating Cells (TICs) that exhibit an enhanced G-CSF production. Interestingly, p140Cap affects the TIC compartment by limiting the active β-Catenin intracellular pool, stabilizing the destruction complex. These findings identify a novel role of p140Cap in preventing the development of an immunosuppressive tumor promoting microenvironment in Breast Cancer.
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Project description:Metastasis is considered to be the final and fatal stage of cancer progression. However, some evidence seems to indicate that tumor cell dissemination could occur early in the natural history of cancer progression. Early disseminated tumor cells (DTC) have been described in the bone marrow (BM) of patients suffering from diverse types of solid tumors as well as in experimental models. The presence of early DTC - which share many features of dormant tumor cells - was found to correlate with later development of metastasis in several cancer types. However, little is known about the tumorigenic features of DTC obtained at different time points along tumor progression. Here, we investigated the actual tumorigenic capacities of DTC. We found that early DTC obtained from BM of 15-17 week-old Her2-neu transgenic (BALB-neuT) mice were not tumorigenic in immunodeficient mice. In contrast, DTC-derived tumors were easily obtained (44 % frequency) when DTC from 19-22 week-old BALB-neuT mice (late DTC) were injected. Angiogenesis, which can contribute to regulate tumor dormancy in other systems, appeared dispensable to reactivate late DTC, although it accelerated growth of secondary DTC tumors. Gene expression profiling disclosed a distinctive transcriptional signature of late DTC tumors compared with that of mammary tumors, which was enriched for hypoxia-related transcripts and appeared to be maintained in cell culture ex-vivo. Immunohistochemical analysis confirmed high HIF-1α expression in DTC tumors, which was maintained in tumor-derived in vitro cultures. Altogether, these findings highlight a different tumorigenic potential of early and late DTC in the BALB-neuT model and describe a HIF-1α-related transcriptional signature in DTC tumors, which may render DTC angiogenesis-competent, when placed in a favourable environment.
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Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.
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