PXD029529-2

PXD029529 is an original dataset announced via ProteomeXchange.

Title	CD81 facilitates tumor cell clustering and metastasis in triple negative breast cancer
Description	Tumor-initiating cells with reprogramming plasticity and/or de-differentiation attributes have been thought to initiate primary tumor development as well as to regenerate secondary tumors in metastatic organs; however, the molecular mechanisms are not fully understood. We previously found that breast tumor-initiating cell marker, CD44, directs multicellular aggregation and cluster formation of circulating tumor cells (CTCs), which further enhance stemness and survival of such cells, enabling metastatic colonization to the lungs. To further elucidate the molecular network underlying CTC cluster formation, we performed global proteomic profiling and discovered that the tetraspanin protein CD81, which is normally enriched in exosomes (small extracellular vesicles), is a new driver of cancer initiation and metastasis as a facilitator and target of CD44. Loss of CD81 compromises tumorigenicity and mammosphere formation of triple negative breast cancer (TNBC) cells. Assisted by machine learning-based algorithms and mutagenesis approach, we found that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. Notably, genetic knockout of CD44 or CD81 results in loss of both CD81 and CD44 in secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells, such as mammosphere formation. In addition, RNA sequencing analysis showed that CD81 knockdown up-regulates expression of a cell differentiation marker, SEMA7a, whose down-regulation partially rescues mammosphere formation inhibition by CD81 depletion. Clinically, CD81 expression was observed in >80% of CTCs and specifically enriched and co-expressed along with CD44 in clustered CTCs of breast cancer patients. Mimicing the phenotypes of CD44 deficiency, loss of CD81 also inhibited tumor cell aggregation and lung metastasis of TNBC in both human and mouse tumor models, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights a new driving role of CD81 in cancer exosome-induced stemness, clustered CTCs, and metastasis initiation of TNBC, reported for the first time to our knowledge.
HostingRepository	jPOST
AnnounceDate	2022-10-18
AnnouncementXML	Submission_2022-11-21_08:25:00.474.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chia-Feng Tsai
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; L-methionine sulfoxide; TMT; TMT; O-phospho-L-serine; O-phospho-L-threonine; O4'-phospho-L-tyrosine; alpha-amino acetylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-02 11:25:39	ID requested
1	2022-10-18 08:42:08	announced
⏵ 2	2022-11-21 08:25:01	announced	2022-11-22: Updated PubMed.

Ramos EK, Tsai CF, Jia Y, Cao Y, Manu M, Taftaf R, Hoffmann AD, El-Shennawy L, Gritsenko MA, Adorno-Cruz V, Schuster EJ, Scholten D, Patel D, Liu X, Patel P, Wray B, Zhang Y, Zhang S, Moore RJ, Mathews JV, Schipma MJ, Liu T, Tokars VL, Cristofanilli M, Shi T, Shen Y, Dashzeveg NK, Liu H, Machine learning-assisted elucidation of CD81-CD44 interactions in promoting cancer stemness and extracellular vesicle integrity. Elife, 11():(2022) [pubmed]

submitter keyword: circulating tumor cells, triple negative breast cancer, CD81

Huiping Liu
lab head
Chia-Feng Tsai
contact affiliation	Pacific Northwest National Laboratory
dataset submitter

jPOST dataset URI

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