Proteomics

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A multi-omic analysis implicates the acquisition of CCDC88A/GIV through tumor-stroma tunnels in escape from tumor cell dormancy


ABSTRACT: Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. Using a co-culture model, we performed an integrated transcriptomic and proteomic analysis of processes induced in ER+ breast cancer cells by close contact with MSCs, but not merely by conditioned media. Computational approaches identified a 52-protein/mRNA ‘signature’ which stratified patients at high risk for relapse, and implicated long-distance intercellular transport via tunneling nanotubes (TNTs) as a means for their ‘acquisition’ by the tumor cell from MSCs. Bioinformatic analyses helped prioritize one gene/protein, CCDC88A/GIV, a multi-functional adapter protein known to drive metastasis. MSCs upregulated GIV in ER+ breast cancer cells through connexin 43-mediated intercellular transport. Stable expression of GIV conferred resistance to clinical anti-estrogen drugs, enhanced tumor dissemination, and recapitulated the 52-gene signature. These data establish a new multi-omic resource for the regulation of breast cancer by MSCs via intercellular transport and validate as proof-of-concept how one transported protein, GIV, orchestrates aggressive disease states.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Mesenchymal Cell

DISEASE(S): Breast Cancer

SUBMITTER: Majid Ghassemian  

LAB HEAD: Pradipta Ghosh1

PROVIDER: PXD039860 | Pride | 2024-07-02

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
All_protein-peptides.csv Csv
All_proteins.csv Csv
PG_TMT10_121422_01.raw Raw
PG_TMT10_121422_02.raw Raw
PG_TMT10_121422_03.raw Raw
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Publications

Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels.

Sinha Saptarshi S   Callow Brennan W BW   Farfel Alex P AP   Roy Suchismita S   Chen Siyi S   Rajendran Shrila S   Buschhaus Johanna M JM   Espinoza Celia R CR   Luker Kathryn E KE   Ghosh Pradipta P   Luker Gary D GD  

bioRxiv : the preprint server for biology 20240810


Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by  ...[more]

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