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AKT dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype [2016]

ABSTRACT: Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE136218 | GEO | 2020/07/29

REPOSITORIES: GEO

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AKT dependent Notch3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype

Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

2021-09-08 | PXD014778 | Pride

AKT dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype [2015]

2020-07-29 | GSE136254 | GEO

Patient-derived xenograft model identifies clinically relevant subtype-specific features of colorectal cancer

Project description:Colorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.

2018-10-16 | GSE103340 | GEO

ERK1/2 controlled genes ANGPT2 and CXCR4 mediate liver metastasis from colon cancer

Project description:Carcinoma development in colorectal cancer (CRC) is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of CRC metastatic disease, but how RAS-ERK signaling regulates CRC metastasis is still unknown. An unbiased screening approach based on selection of highly liver metastatic CRC cells in vivo was used to determine genes associated with metastasis and a ERK1/2-controlled metastatic gene set (EMGS) defined. The ANGPT2 and CXCR4, two genes within the gene set, were subjected to gain and loss of function validation in CRC cells (SW620, SW480, Colo26, HCT116), its downstream mechanism validated, and tested in clinical samples. Here, we identified an EMGS that is associated with increased recurrence and reduced survival for patients with CRC tumors. Higher levels of EMGS expression were detected in the CRC subsets Consensus Molecular Subtype (CMS)1 and CMS4. We show that the RAS-ERK1/2 axis controls the expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in CRC cells, and that this facilitates the development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are essential for metastatic outgrowth in the liver. We also show that CXCR4 also controls the expression of the cytokines IL10 and CXCL1, and provide evidence for a causal role of IL10 in supporting liver colonization. In summary, we demonstrate that amplification of ERK1/2 signaling in KRAS-mutated CRC cells affects the cytokine milieu of the tumors, thus possibly affecting tumor?stroma interactions and favoring liver metastasis formation.

2020-07-31 | GSE142219 | GEO

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses

Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.

2019-02-28 | PXD012650 | Pride

LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3

Project description:The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unravel a novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2 and LoVo) with either knockdown or overexpression of LIN28B, we identified Claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and post-transcriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA-sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B-CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by post-transcriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.

2023-09-14 | GSE234513 | GEO

Peritoneal Metastases from Colorectal Cancer belong to Consensus Molecular Subtype 4 and are sensitized to oxaliplatin by inhibiting reducing capacity

Project description:Background: Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance. Experimental design: We generated a biobank consisting of 35 primary tumor regions and 59 paired PM from 12 patients. All samples were analyzed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin Results: PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumors belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitized PMDOs to a 1-hour exposure to oxaliplatin, through increased platinum-DNA adduct formation Conclusions: These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin

2022-06-15 | GSE190609 | GEO

Consensus molecular subtype transition during progression of colorectal cancer [Tumor Signaling 360™ Panel]

Project description:The consensus molecular subtype (CMS) classification divides colorectal cancer (CRC) into four distinct subtypes based on RNA-expression profiles. The biological differences between CMSs are already present in CRC precursor lesions, but not all CMSs pose the same risk of malignant transformation. To fully understand the path to malignant transformation and to determine whether CMS is a fixed entity during progression, genomic and transcriptomic data from two regions of the same CRC lesion were compared: the precursor and carcinoma region. In total, 24 patients that underwent endoscopic removal of T1-2 CRC were included. Regions were subtyped for CMS and DNA mutation analysis was performed. Additionally, a set of 85 benign adenomas was CMS subtyped. This analysis revealed that almost all benign adenomas were classified as CMS3 (91.8%). In contrast, CMS2 was the most prevalent subtype in precursor regions (66.7%), followed by CMS3 (29.2%). CMS4 was absent in precursor lesions and originated at the carcinoma stage. Importantly, CMS switching occurred in a substantial number of cases and almost all (6 out of 7) CMS3 precursor regions showed a shift to a different subtype in the carcinoma part of the lesion, which in 4 cases was classified as CMS4. In conclusion, our data indicate that CMS3 is related to a more indolent type of precursor lesions that less likely progresses to CRC and when this occurs it often associates with a subtype change that includes the more aggressive mesenchymal CMS4. In contrast, an acquired CMS2 signature appeared to be rather fixed during early CRC development. Combined our data shows that subtype changes occur during progression and that CMS3 switching is related to changes in the genomic background through acquisition of a novel driver mutation (TP53) or selective expansion of a clone, but also occurred independent of such genetic changes.

2023-07-13 | GSE237248 | GEO

Consensus molecular subtype transition during progression of colorectal cancer [NanoClassifier Gene Set]

2023-07-13 | GSE237247 | GEO

Proteome Profiling Identifies Markers for Inflammation-Related Tumor-Fibroblast Interaction in Colorectal Cancer

Project description:Inflammation has been identified as an important factor in cancer development and progression, including colorectal cancer [CRC]. To determine the role of inflammation and the specific contribution of activated fibroblasts in cancer development and progression we analyzed six human CRC tissue specimens and paired normal adjacent mucosa samples by LS/MS-MS. Amongst other, indeed several inflammation associated proteins were found differentially expressed compared to normal colonic mucosa. Two candidate molecules, SPARC and THBS2 were recently identified as proteins of a fibroblast inflammation signature. Analysis of public available RNA expression datasets revealed, that the mRNA of both SPARC and THBS2 are upregulated in CRC, typically in association with the CRC consensus molecular subtype 4 [CMS4]. Immunohistochemistry staining also demonstrated upregulation of SPARC and THBS2 in the tumor stroma compared to normal adjacent mucosa and indicated co-localization with the mesenchymal marker [alpha]SMA. In vitro 3D co-culture experiments with human colon derived fibroblasts and CRC cell lines resulted in enhanced SPARC and THBS2 protein levels when both cell types were cultivated in direct physical contact, compared to fibroblasts or cancer cells alone. This study demonstrates the feasibility of detecting tumor-specific signatures by LC-MS/MS and compatibility with RNA expression datasets. We identified an inflammation signature in CRC tissue and the data emphasized the contribution of activated fibroblasts in these events.

2018-10-17 | PXD006776 | Pride

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