Dataset Information

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

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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Julia Varga

LAB HEAD: Florian R. Greten

PROVIDER: PXD014778 | Pride | 2021-09-08

REPOSITORIES: Pride

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Publications

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer.

Varga Julia J Nicolas Adele A Petrocelli Valentina V Pesic Marina M Mahmoud Abdelrahman A Michels Birgitta E BE Etlioglu Emre E Yepes Diego D Häupl Björn B Ziegler Paul K PK Bankov Katrin K Wild Peter J PJ Wanninger Stefan S Medyouf Hind H Farin Henner F HF Tejpar Sabine S Oellerich Thomas T Ruland Jürgen J Siebel Christian W CW Greten Florian R FR

The Journal of experimental medicine 20201001 10

Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of 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 tumor invasion and metastasis in Trp53ΔIE ...[more]

PMID: 32749453

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Project description:High-throughput genomic studies have identified thousands of genetic alterations in colorectal cancer (CRC). Distinguishing driver from passenger mutations is critical for developing rational therapeutic strategies. Because only a few transcriptional subtypes exist in previously studied tumor types, we hypothesize that highly heterogeneous genomic alterations may converge to a limited number of distinct mechanisms that drive unique gene expression patterns in different transcriptional subtypes. In this study, we defined transcriptional subtypes for CRC and identified driver networks/pathways for each subtype, respectively. Applying consensus clustering to a patient cohort with 1173 samples identified three transcriptional subtypes, which were validated in an independent cohort with 485 samples. The three subtypes were characterized by different transcriptional programs related to normal adult colon, early colon embryonic development, and epithelial mesenchymal transition, respectively. They also showed statistically different clinical outcomes. For each subtype, we mapped somatic mutation and copy number variation data onto an integrated signaling network and identified subtype-specific driver networks using a random walk-based strategy. We found that genomic alterations in the Wnt signaling pathway were common among all three subtypes; however, unique combinations of pathway alterations including Wnt, VEGF, Notch and TGF-beta drove distinct molecular and clinical phenotypes in different CRC subtypes. Our results provide a coherent and integrated picture of human CRC that links genomic alterations to molecular and clinical consequences, and which provides insights for the development of personalized therapeutic strategies for different CRC subtypes. To characterize the embryonic development of colon, we conducted a time course microarray study using the inbred C57BL/6 (Jackson Laboratories, Bar Harbor, ME) mice. Seven samples corresponding to the mouse colonic development from E13.5 to E18.5 and adult (eight week post-natal) were collected. RNA samples were submitted to the Vanderbilt Functional Genomics Shared Resource (FSGR, http://array.mc.vanderbilt.edu), where RNA was hybridized to the Affymetrix Mouse Genome 430 2.0 GeneChip Expression Arrays (Santa Clara, CA) according to manufacturer’s instructions. The RMA algorithm was used for data normalization. Mouse gene symbols were mapped to human gene symbols by the Human and Mouse Orthology list available from the Mouse Genome Informatics (http://www.informatics.jax.org/).

Dataset Information

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

Publications

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer.

Similar Datasets

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