Triple-negative breast cancer (TNBC) is an aggressive and complex subtype of breast cancer that lacks targeted therapy. TNBC manifests characteristic, extensive intratumoral heterogeneity that promotes disease progression and influences drug response. Single-cell techniques in combination with next-generation computation provide an unprecedented opportunity to identify molecular events with therapeutic potential. Here, we describe the generation of a comprehensive mass cytometry panel for multiparametric detection of 23 phenotypic markers and 13 signaling molecules. This single-cell proteomic approach allowed us to explore the landscape of TNBC heterogeneity, with particular emphasis on the tumor microenvironment. We prospectively profiled freshly resected tumors from 26 TNBC patients. These tumors contained phenotypically distinct subpopulations of cancer and stromal cells that were associated with the patient's clinical status at the time of surgery. We further classified the epithelial-mesenchymal plasticity of tumor cells, and molecularly defined phenotypically diverse populations of tumor-associated stroma. Furthermore, in a retrospective tissue-microarray TNBC cohort, we showed that the level of CD97 at the time of surgery has prognostic potential.
- Klíčová slova
- mass cytometry, phenotypic plasticity, single-cell profiles, triple-negative breast cancer, tumor heterogeneity, unsupervised machine learning algorithm,
- MeSH
- buňky stromatu metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí MeSH
- proteomika MeSH
- retrospektivní studie MeSH
- signální transdukce MeSH
- triple-negativní karcinom prsu * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The progenitors to lung airway epithelium that are capable of long-term propagation may represent an attractive source of cells for cell-based therapies, disease modeling, toxicity testing, and others. Principally, there are two main options for obtaining lung epithelial progenitors: (i) direct isolation of endogenous progenitors from human lungs and (ii) in vitro differentiation from some other cell type. The prime candidates for the second approach are pluripotent stem cells, which may provide autologous and/or allogeneic cell resource in clinically relevant quality and quantity. METHODS: By exploiting the differentiation potential of human embryonic stem cells (hESC), here we derived expandable lung epithelium (ELEP) and established culture conditions for their long-term propagation (more than 6 months) in a monolayer culture without a need of 3D culture conditions and/or cell sorting steps, which minimizes potential variability of the outcome. RESULTS: These hESC-derived ELEP express NK2 Homeobox 1 (NKX2.1), a marker of early lung epithelial lineage, display properties of cells in early stages of surfactant production and are able to differentiate to cells exhibitting molecular and morphological characteristics of both respiratory epithelium of airway and alveolar regions. CONCLUSION: Expandable lung epithelium thus offer a stable, convenient, easily scalable and high-yielding cell source for applications in biomedicine.
- Klíčová slova
- Differentiation, Epithelium, Foregut endoderm, Lung, hESC,
- MeSH
- buněčná diferenciace MeSH
- epitel MeSH
- lidé MeSH
- lidské embryonální kmenové buňky * MeSH
- plíce metabolismus MeSH
- povrchově aktivní látky metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- povrchově aktivní látky MeSH
Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.
- Klíčová slova
- TACSTD2, Trop2, cancer, epithelial-to-mesenchymal transition, metastases, proliferation, therapy,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The epithelial-mesenchymal plasticity, in tight association with stemness, contributes to the mammary gland homeostasis, evolution of early neoplastic lesions and cancer dissemination. Focused on cell surfaceome, we used mouse models of pre-neoplastic mammary epithelial and cancer stem cells to reveal the connection between cell surface markers and distinct cell phenotypes. We mechanistically dissected the TGF-β family-driven regulation of Sca-1, one of the most commonly used adult stem cell markers. We further provided evidence that TGF-β disrupts the lineage commitment and promotes the accumulation of tumor-initiating cells in pre-neoplastic cells.
- MeSH
- ataxin-1 metabolismus MeSH
- epitelo-mezenchymální tranzice genetika MeSH
- epitelové buňky patologie MeSH
- experimentální nádory mléčných žláz genetika patologie MeSH
- lidé MeSH
- mléčné žlázy zvířat patologie MeSH
- myši MeSH
- nádorové buněčné linie transplantace MeSH
- nádorové kmenové buňky patologie MeSH
- nádory prsu genetika patologie MeSH
- plasticita buňky genetika MeSH
- receptor erbB-2 genetika MeSH
- regulace genové exprese u nádorů MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- signální transdukce genetika MeSH
- transformující růstový faktor beta genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ataxin-1 MeSH
- Atxn1 protein, mouse MeSH Prohlížeč
- Erbb2 protein, mouse MeSH Prohlížeč
- receptor erbB-2 MeSH
- rekombinantní proteiny MeSH
- transformující růstový faktor beta MeSH
