Dataset Information

CD81 facilitates tumor cell clustering and metastasis in triple negative breast cancer

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Huiping Liu

PROVIDER: PXD029529 | JPOST Repository | Tue Oct 18 00:00:00 BST 2022

REPOSITORIES: jPOST

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			Action	DRS
	NW_siCD81_Plex01_P_f02_02Jun21_Pippin_Rep-21-02-07.raw	Raw
	NW_siCD81_Plex01_P_f02_Rep2_04Jun21_Pippin_Rep-21-02-07.raw	Raw
	NW_siCD81_Plex01_P_f03_02Jun21_Pippin_Rep-21-02-07.raw	Raw
	NW_siCD81_Plex01_P_f03_Rep2_04Jun21_Pippin_Rep-21-02-07.raw	Raw
	NW_siCD81_Plex01_P_f04_02Jun21_Pippin_Rep-21-02-07.raw	Raw

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Publications

Machine learning-assisted elucidation of CD81-CD44 interactions in promoting cancer stemness and extracellular vesicle integrity.

Ramos Erika K EK Tsai Chia-Feng CF Jia Yuzhi Y Cao Yue Y Manu Megan M Taftaf Rokana R Hoffmann Andrew D AD El-Shennawy Lamiaa L Gritsenko Marina A MA Adorno-Cruz Valery V Schuster Emma J EJ Scholten David D Patel Dhwani D Liu Xia X Patel Priyam P Wray Brian B Zhang Youbin Y Zhang Shanshan S Moore Ronald J RJ Mathews Jeremy V JV Schipma Matthew J MJ Liu Tao T Tokars Valerie L VL Cristofanilli Massimo M Shi Tujin T Shen Yang Y Dashzeveg Nurmaa K NK Liu Huiping H

eLife 20221004

Tumor-initiating cells with reprogramming plasticity or stem-progenitor cell properties (stemness) are thought to be essential for cancer development and metastatic regeneration in many cancers; however, elucidation of the underlying molecular network and pathways remains demanding. Combining machine learning and experimental investigation, here we report CD81, a tetraspanin transmembrane protein known to be enriched in extracellular vesicles (EVs), as a newly identified driver of breast cancer ...[more]

PMID: 36193887

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