PXD034037

PXD034037 is an original dataset announced via ProteomeXchange.

Title	The Yin and Yang of GDF15: a secreted biomarker of eribulin response in breast cancer cells, yet required for survival of drug tolerant persister (DTP) cells
Description	Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:00:34.297.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Francesc Canals
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-24 08:24:12	ID requested
1	2023-01-09 09:12:54	announced
⏵ 2	2023-11-14 08:00:35	announced	2023-11-14: Updated project metadata.

Bellio C, Emperador M, Castellano P, Gris-Oliver A, Canals F, S, á, nchez-Pla A, Zamora E, Arribas J, Saura C, Serra V, Tabernero J, Littlefield BA, Villanueva J, GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells. Cancers (Basel), 14(10):(2022) [pubmed]

submitter keyword: eribulin,Drug tolerance, growth differentiation factor (GDF15), secretome., Drug tolerant persister (DTP), breast cancer (BC)

Josep Villanueva
contact affiliation	Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
contact email	jvillanueva@vhio.net
lab head
Francesc Canals
contact affiliation	Vall Hebron Institute of Oncology
contact email	fcanals@vhio.net
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034037
     1. Label: PRIDE project
     2. Name: The Yin and Yang of GDF15: a secreted biomarker of eribulin response in breast cancer cells, yet required for survival of drug tolerant persister (DTP) cells