PXD053108

PXD053108 is an original dataset announced via ProteomeXchange.

Title	Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response
Description	Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-06_19:32:08.486.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD053108
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Jennifer Bethard
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-14 03:27:47	ID requested
⏵ 1	2025-05-06 19:32:09	announced

10.1016/j.celrep.2024.114532;

Wofford W, Kim J, Kim D, Janneh AH, Lee HG, Atilgan FC, Oleinik N, Kassir MF, Saatci O, Chakraborty P, Tokat UM, Gencer S, Howley B, Howe P, Mehrotra S, Sahin O, Ogretmen B, Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. Cell Rep, 43(8):114532(2024) [pubmed]

10.6019/PXD053108;

submitter keyword: Sonic-Hedgehog,Ceramide, Sphingolipid, CerS4, PD-L1, Metastasis, Immunotherapy

Besim Ogretmen
contact affiliation	Department of Biochemistry and Molecular Biology Hollings Cancer Center Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425;
contact email	ogretmen@musc.edu
lab head
Jennifer Bethard
contact affiliation	Medical University of SC
contact email	bethard@musc.edu
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/2025/05/PXD053108

PRIDE project URI

• PRIDE
  1. PXD053108
     1. Label: PRIDE project
     2. Name: Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response