PXD014778-2

PXD014778 is an original dataset announced via ProteomeXchange.

Title	AKT dependent Notch3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:26:26.664.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Julia Varga
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-26 07:29:11	ID requested
1	2019-09-25 06:04:24	announced
⏵ 2	2024-10-22 05:26:27	announced	2024-10-22: Updated project metadata.

10.1084/jem.20191515;

Varga J, Nicolas A, Petrocelli V, Pesic M, Mahmoud A, Michels BE, Etlioglu E, Yepes D, H, ä, upl B, Ziegler PK, Bankov K, Wild PJ, Wanninger S, Medyouf H, Farin HF, Tejpar S, Oellerich T, Ruland J, Siebel CW, Greten FR, AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer. J Exp Med, 217(10):(2020) [pubmed]

submitter keyword: Label-free quantification,Colorectal cancer, LC/MS, Protein phosphorylation

Florian R. Greten
contact affiliation	Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
contact email	greten@gsh.uni-frankfurt.de
lab head
Julia Varga
contact affiliation	Georg-Speyer-Haus
contact email	varga@gsh.uni-frankfurt.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/09/PXD014778

PRIDE project URI

• PRIDE
  1. PXD014778
     1. Label: PRIDE project
     2. Name: AKT dependent Notch3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype