Mus musculus
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ABSTRACT:
PROVIDER: PRJNA296370 | ENA |
REPOSITORIES: ENA
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Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction
2015-09-19 | E-GEOD-73208 | biostudies-arrayexpress
Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling.
2015-09-19 | GSE73208 | GEO
Project description:Genes that mediate colorectal cancer liver metastasis
| PRJNA144399 | ENA
Project description:VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain still unclear. In our study, we found that increased expression of YB1 (Y box binding protein 1, a multidrug resistance associated protein) and EphA2 (a member of erythropoietin-producing hepatocellular (Eph) receptors, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells and suppressed tumor growth in vivo and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stabilization of EphA2 through inhibiting the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.
2020-05-28 | GSE151336 | GEO
Project description:Colorectal cancer is one of the most frequently occurring malignancies and a major cause of cancer death. Distant metastases in this disease most commonly develop in the liver and are often untreatable. Here, we show that citrullination of the extracellular matrix (ECM) by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases. Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is well recognized in rheumatoid arthritis, but largely undocumented in cancer. PAD4, a key enzyme responsible for catalyzing citrullination, is produced by metastatic colorectal cancer cells and found at higher levels in human liver metastases than in normal liver. Functional significance for citrullination in metastatic growth was evident in murine models where inhibition of citrullination, either globally by pharmacologic inhibition of PADs or specifically in colorectal cancer cells by PAD4 knockdown substantially reduced liver metastatic burden. Additionally, citrullination of a key ECM component collagen type I led to greater adhesion and decreased migration of colorectal cancer cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition (MET) and liver metastasis. Overall, our study revealed the potential for PAD4-dependant citrullination to drive the progression of liver metastasis. These data indicate that inhibition of citrullination could be exploited to prevent the development of liver metastases in colorectal cancer.
2018-10-18 | PXD010252 | Pride
Project description:Despite advances, treatment of unresectable colorectal cancer remains a clinical challenge and the incidence of this malignancy is increasing in individuals below the age of fifty. Integrated genomic, transcriptomic, proteomic, and mechanistic studies identified the tyrosine kinase receptors EphB2 and EphB4 as colorectal cancer drivers, and EphA2 activity as a cancer resistance mechanism to epidermal growth factor receptor and BRAF inhibitors. Reduction of EphB2 and EphB4 activity suppresses colorectal cancer cell growth and survival and is a potential target for colorectal cancer therapy. Here, we report the design and synthesis of two novel inhibitors, 1 and 3, that selectively bind with high affinity to A and B-type Eph receptor tyrosine kinases, inhibit A and B-type Eph tyrosine kinase activity, induce cell cycle arrest and confer a protracted state of growth reduction to colorectal cancer cells. 1 and 3 bind to EphA2 arresting the activation loop containing the conserved Asp-Phe-Gly (“DFG”)-motif in an inactive conformation and show a conserved hydrogen bond interaction with the so-called gatekeeper residue, the activation loop, alphaC helix, and hinge region of the kinase, typical of kinase inhibitors. These results demonstrate that pharmacological inhibition of Eph tyrosine kinase receptors is a valid therapeutic approach for the treatment of colorectal cancer.
2024-05-23 | PXD031880 | Pride
Project description:Patients with the microsatellite stable (MSS) subset of colorectal cancer, which accounts for 85-90% of all human colorectal cancer cases, do not respond to PD-(L)1 immune checkpoint inhibitor immunotherapy. Metastasis accounts for over 90% of human colorectal cancer mortality and liver metastasis accounts for 90% of human colorectal cancer metastasis. The mechanism underlying colorectal tumor cell immune evasion and the resultant liver metastasis is incompletely understood. The SUV39H1-H3K9me3 epigenetic pathway has emerged as a key regulator of CTL persistence and effector function in anti-tumor immunity. We therefore aimed at testing the hypothesis that H3K9me3 induces CTL dysfunction to promote colorectal tumor liver metastasis. Using a mouse MSS colon tumor experimental liver metastasis model, we observed that PD-1 blockade immunotherapy does not induce CTL activation in the liver metastases and exhibits no significant efficacy in suppression of liver metastasis. CTL adaptive transfer increased accumulation of the tumor-specific CTLs in liver metastases but also exhibited no significant efficacy in suppression of liver metastasis. However, pharmacological inhibition of H3K9me3-specific histone methyltransferases with the small molecule F5446 significantly suppressed liver metastasis in mice. scRNA-seq analysis of liver metastases-infiltrating immune cells revealed that F5446 therapy does not increased total level of T cell tumor infiltration. Instead, inhibition of H3K9me3 increased Tex and decreased Tcm in liver metastases. Analysis of human colon tumor scRNA-Seq datasets identified Tex, Tcm and Tem-like clusters in both primary and liver metastasis with higher level of Tex subset of T cells in liver metastases than primary tumor. Our findings determine that colon tumor cells induce H3K9me3 to regulate T cell differentiation and effector function in liver metastases microenvironment and targeting H3K9me3 is a promising approach for suppression of CRC liver metastasis.
2025-07-15 | GSE302202 | GEO
Project description:Prostate cancer morbidity and mortality obviate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo. To further explore this complexity, we performed detailed phosphoproteomic analysis following ligand-induced EphA2 activation. Our analysis identified altered phosphorylation of 73 downstream proteins related to the PI3K/AKT/mTOR and ERK/MAPK pathways, with the majority implicated in cell junction and cytoskeletal organization, cell motility, and tumor metastasis. We demonstrate that the adaptor protein SHB is an essential component in mediating the inhibition of the Erk/MAPK pathway in response to EphA2 receptor activation. Furthermore, we identify the adherence junction protein afadin as an EphA2-regulated phosphoprotein which is involved in prostate cancer migration and invasion.
2024-11-11 | PXD053835 | Pride
Project description:Ovarian cancer develops early intra-peritoneal metastasis establishing a pro-tumorigenic tumor microenvironment (TME) through reprogramming normal mesenchymal stem cells into carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are the stromal stem cell of the TME, supporting cancer growth, increasing desmoplasia, angiogenesis and chemotherapy resistance. We demonstrate epigenetic rewiring drives CA-MSC formation via enhancer-enriched DNA hypermethylation, altered chromatin accessibility and differential histone modifications inducing a partial mesenchymal to epithelial transition (MET) increasing tumor cell adhesion. Direct CA-MSC:tumor cell interactions, confirmed in patient ascites, facilitate ovarian cancer metastasis through co-migration. WT1, a developmental mediator of MET, and EZH2, mediate CA-MSC epigenetic reprogramming. WT1 overexpression induces CA-MSC conversion while WT1 knock-down, in combination with EZH2 inhibition, blocks CA-MSC formation. EZH2 inhibition subsequently decreases intra-abdominal metastasis.
2020-12-22 | GSE138072 | GEO
Project description:Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in ES cells via ligand-dependent signaling. EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897), has been linked to metastasis in several malignancies. Here, we stablish a correlation between ES cells aggressiveness and p-EphA2S897. Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a nonphosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.
2018-04-11 | GSE106480 | GEO