The Disabled homolog 2 controls pro-metastatic activity of tumor-associated macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA640048 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12033524_1.fastq.gz | Fastqsanger.gz | |||
| SRR12033524_2.fastq.gz | Fastqsanger.gz | |||
| SRR12033525_1.fastq.gz | Fastqsanger.gz | |||
| SRR12033525_2.fastq.gz | Fastqsanger.gz | |||
| SRR12033526_1.fastq.gz | Fastqsanger.gz |
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Project description:Hypoxia controls the glycobiological signature and related pro-tumorigenic properties of metastatic melanomas
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Project description:The liver is the most common site of metastatic disease in gastrointestinal malignancies, including pancreatic ductal adenocarcinoma (PDAC). While this metastatic tropism may reflect mechanical trapping of tumor cells that enter the circulation, liver metastasis is also dependent, at least in part, on the formation of a “pro-metastatic” niche that supports tumor cell seeding and colonization in the liver. However, mechanisms that orchestrate the establishment of this niche are poorly understood. Here, we show that hepatocytes coordinate accumulation of myeloid cells and fibrosis within the liver, the two defining features of a pro-metastatic niche. Early during pancreatic tumorigenesis in mice, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in PDAC patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells that reside adjacent to malignant cells in the pancreas. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling in hepatocytes effectively prevents the establishment of a pro-metastatic niche and inhibits metastatic seeding in the liver. Collectively, our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets for pancreatic cancer.
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Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population reference x sample
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Project description:How cells in primary tumors initially become pro-metastatic is not understood. A previous genome-wide RNAi screen uncovered colon cancer metastatic suppressor and WNT promoting functions of TMED3, a member of the p24 ER-to-Golgi protein secretion family. Repression of WNT signaling upon knock-down (kd) of TMED3 might thus be sufficient to drive metastases. However, searching for transcriptional influences on other family members here we find that TMED3 kd leads to enhanced TMED9, that TMED9 acts downstream of TMED3 and that TMED9 kd compromises metastasis. Importantly, TMED9 pro-metastatic function is linked to but distinct from the repression of TMED3-WNT-TCF signaling. Functional rescue of the migratory deficiency of TMED9 kd cells identifies TGFa as a mediator of TMED9 pro-metastatic activity. Moreover, TMED9 kd compromises the membrane localization, and thus function, of TGFa. Analyses in three colon cancer cell types highlight a TMED9-dependent gene set that includes CNIH4, a member of the CORNICHON family of TGFa exporters. Our data indicate that TGFA and CNIH4, which display predictive value for disease-free survival, promote colon cancer cell metastatic behavior and suggest that TMED9 pro-metastatic function involves the modulation of the secretion of TGFa ligand. Finally, TMED9/TMED3 antagonism impacts WNT-TCF and GLI signaling, where TMED9 primacy over TMED3 leads to the establishment of a positive feedback loop together with CNIH4, TGFa and GLI1 that enhances metastases. We suggest that primary colon cancer cells can transition between two states characterized by secretion-transcription regulatory loops gated by TMED3 and TMED9 that modulate their metastatic proclivities.
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Project description:Metastatic melanoma (MM) has a five-year survival rate of only 37%. The major causes of MM-related mortality are distant organ involvement and treatment resistance. These metastatic activities are often potentiated by the persistence of tumor-initiating cells (TICs) thriving in areas of hypoxia. To enhance therapy success, it is, thus, critical to understand MM TIC properties and devise MM TIC-specific treatment strategies. Our recent data suggest that MM cells have a distinct MM glycome signature characterized by fetal i-linear poly-N-acetyllactosamines (poly-LacNAc) and loss of I-branching enzyme β1,6 N-acetylglucosaminyltransferase 2 (GCNT2) that promote tumorigenicity. Whether hypoxia can instruct MM TIC development by modulating the MM glycome signature remains unknown. Here, comparative analysis of GCNT2 levels on patient melanoma cells and clinical outcome confirmed the relationship between loss of GCNT2 and poor patient survival. Moreover, MM cells with low GCNT2 showed elevated TIC marker expression and increased TIC potential, in vivo. Under hypoxia, MM cells further lost GCNT2 and I-branched poly-LacNAc expression and showed corresponding elevations in TIC markers and other glycome-related alterations. Galectin (Gal)-8, notably, was upregulated under hypoxia, preferred binding to i-linear poly-LacNAcs, increased TIC marker CD271, and was significantly elevated in sera of melanoma patients. Knockdown of Gal-8 in MM cells significantly decreased CD271 levels, even under hypoxia. Results from this investigation reveal a key role for hypoxia in enforcing the MM glycome signature and for Gal-8 as a pro-tumorigenic lectin and putative biomarker of MM.
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Project description:Tumor-derived exosomes are emerging as mediators of tumorigenesis with a tissue-specific address and message. We explored the function of melanoma-derived exosomes in formation of primary tumors and metastatic progression in both murine models and patients. Whereas exosomes from highly metastatic melanoma cells increased the metastatic behavior of primary tumor cells by educating bone marrow (BM) progenitor cells via the MET receptor, exosomes from low metastatic melanoma cells did not alter the incidence of metastases. Melanoma-derived exosomes induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitor cells towards a pro-vasculogenic phenotype (c-Kit+Tie2+MET+). Reducing MET expression in tumor-derived exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was upregulated in circulating BM progenitor cells (CD45-CD117low and CD45-CD117lowTIE2+) isolated from stage III and stage IV melanoma patients. Rab1a, Rab5b, Rab7, and Rab27a were highly expressed in melanoma and Rab27a RNA interference decreased exosome production and/or soluble angiogenic factors in melanoma cells, thereby preventing mobilization of BM progenitor cells, tumor growth and metastasis. Finally, we identified a melanoma signature in exosomes isolated from metastatic melanoma patients, comprised of TYRP2, VLA-4, Hsp70, an Hsp90 isoform and MET oncoprotein, which together with Rab proteins, appear to represent exosome-specific proteins with prognostic potential, and may provide new therapeutic targets. Identification of molecular finger associated to exosome effects in metastatic organs Microarray analysis of genes differentially expressed in the lungs 24 and 48 hours after B16-F10 exosome tail vein injection compared to control.
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Project description:The tetraspanin CD63 is implicated in pro-metastatic signaling pathways, but so far, it is unclear how CD63 levels affect the tumor cell phenotype. Here, we investigated the effect of CD63 modulation in different metastatic tumor cell lines. In vitro, knock down of CD63 induced a more epithelial-like phenotype concomitant with increased E-cadherin expression, downregulation of its repressors Slug and Zeb1, and decreased N-cadherin. In addition, β-catenin protein was markedly reduced, negatively affecting expression of the target genes MMP-2 and PAI-1. β-catenin inhibitors mimicked the epithelial phenotype induced by CD63 knock down. Inhibition of β-catenin upstream regulators PI3K/AKT or GSK3β could rescue the mesenchymal phenotype underlining the importance of the β-catenin pathway in CD63-regulated cell plasticity. CD63 knock down-induced phenotypical changes correlated with a decrease of experimental metastasis, while CD63 overexpression enhanced the tumor cell-intrinsic metastatic potential. Taken together, our data show that CD63 is a crucial player in the regulation of the tumor cell-intrinsic metastatic potential by affecting cell plasticity. Stable knock down of CD63 was performed in SKOV3ipL ovarian carcinoma cell line using 2 shRNAs lentiviral constructs (sh49 and sh51), and as a negative control, a shNT construct. Parental cells, control shNT and the 2 shCD63 cell lines were seeded 24 hours prior to RNA isolation on a 10 cm dish, labelling and hybridization on microarrays. One color experiment with 2 biological replicates of the 4 experimental conditions: SKOV3ipL, SKOV3ipL_shNT, SKOV3ipL_sh49 and SKOV3ipL_sh51.
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