PXD008410-2

PXD008410 is an original dataset announced via ProteomeXchange.

Title	PI3Kinase Isoforms in Pancreatic cancer
Description	Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with a 5 year-survival rate below 5%. Lack of curative treatment and failure of targeted therapies urge the need to identify novel efficient therapeutic strategy. Achievement of this goal will be obtained through the identification of diagnosis and prognosis biomarkers, identification of novel therapeutic targets and the knowledge of resistance mechanisms induced by these targeted therapies. PI3K/Akt/mTOR signalling, one of the most altered in cancers, is overactivated in pancreatic cancer and correlated with poor prognosis. In the Vertebrates, the family of class I phosphoinoitide-3-kinase (PI3K) includes four isoforms: p110α, p110β, p110δ and p110γ. Although they all perform the same biochemical reaction (phosphorylation of PIP2 in PIP3, a membrane lipid messenger), each isoform were demonstrated to have specific physiological roles. Global PI3K inhibitors are currently being tested in phase I/II clinical trials in advanced solid cancers, but show at maximal doses tolerated a limited therapeutic benefit. Isoform-selective PI3K inhibitors are currently the most promising agents because, at low doses, they are more efficient to inhibit one PI3K isoform, and thus, less toxic than pan-PI3K inhibitors. The objectives of this thesis are to determine isoform-specific PI3K roles and the therapeutic interest to target one or more isoforms in pancreatitis and PDAC, by the identification of isoform-specific pathways and the study of adaptive responses induced by targeting of one or all isoforms of PI3K. In a first part, my work has highlighted, validated and completed results obtained in the team, to demonstrate the significance of PI3K/Akt signalling in two physiological processes: chronic pancreatitis and initiation of pancreatic carcinogenesis. Precisely, the overactivation of PI3K/Akt pathway measured on human and murine chronic pancreatitis samples is correlated with a specific p110α activation gene expression signature. Moreover, genetic and pharmacologic inactivation of p110α during pancreatic chronic inflammation or cancerogenesis (by oncogenic Kras) prevents the formation of acino-ductal metaplasia, structures at the origin of pancreatic carcinogenesis initiation. Development of in vitro acino-ductal transdifferentiation protocol allowed me to demonstrate that only p110α is necessary at this initial step of pancreatic carcinogenesis by the regulation of Rho small GTPases, further regulating actin remodelling. In the second part, by a phosphoproteomic-based approach, I quantified PI3K downstream phosphorylation-regulated targets in a pancreatic cancer cell line treated or not by a pan- or selective PI3K inhibitor at different times. I demonstrated for the first time existence of targets, signalling pathways and adaptive responses regulated by each PI3K isoform. To conclude, all these results demonstrate the rational of combinatorial use of isoform-specific PI3K inhibitors in patients with pancreatic cancer for better clinical response
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:34:08.101.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Emmanuelle Mouton Barbosa
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2017-12-11 06:03:49	ID requested
1	2022-02-28 03:19:03	announced
⏵ 2	2024-10-22 05:34:08	announced	2024-10-22: Updated project metadata.

10.1158/1535-7163.mct-20-0981;

Cintas C, Douche T, Dantes Z, Mouton-Barbosa E, Bousquet MP, Cayron C, Therville N, Pont F, Ramos-Delgado F, Guyon C, Garmy-Susini B, Cappello P, Burlet-Schiltz O, Hirsch E, Gomez-Brouchet A, Thibault B, Reichert M, Guillermet-Guibert J, Phosphoproteomics Identifies PI3K Inhibitor-selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance. Mol Cancer Ther, 20(12):2433-2445(2021) [pubmed]

curator keyword: Biomedical

submitter keyword: PI3K Signaling Pathway Isoforms

Guillermet Julie
contact affiliation	Centre de Recherches en Cancérologie de Toulouse; INSERM U1037, team 17 PI3K isoforms, signalling and cancerogenesis
contact email	julie.guillermet@inserm.fr
lab head
Emmanuelle Mouton Barbosa
contact affiliation	IPBS CNRS
contact email	emmanuelle.mouton@ipbs.fr
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/2022/02/PXD008410

PRIDE project URI

• PRIDE
  1. PXD008410
     1. Label: PRIDE project
     2. Name: PI3Kinase Isoforms in Pancreatic cancer