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Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes.
Winkler, Juliane; Tan, Weilun; Diadhiou, Catherine Mm; McGinnis, Christopher S; Abbasi, Aamna; Hasnain, Saad; Durney, Sophia; Atamaniuc, Elena; Superville, Daphne; Awni, Leena; Lee, Joyce V; Hinrichs, Johanna H; Wagner, Patrick S; Singh, Namrata; Hein, Marco Y; Borja, Michael; Detweiler, Angela M; Liu, Su-Yang; Nanjaraj, Ankitha; Sitarama, Vaishnavi; Rugo, Hope S; Neff, Norma; Gartner, Zev J; Oliveira Pisco, Angela; Goga, Andrei; Darmanis, Spyros; Werb, Zena.
Afiliación
  • Winkler J; Department of Anatomy and.
  • Tan W; Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
  • Diadhiou CM; Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • McGinnis CS; Chan Zuckerberg Biohub SF, San Francisco, California, USA.
  • Abbasi A; Department of Anatomy and.
  • Hasnain S; Department of Pharmaceutical Chemistry, UCSF, San Francisco, California, USA.
  • Durney S; Department of Anatomy and.
  • Atamaniuc E; Department of Anatomy and.
  • Superville D; Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
  • Awni L; Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
  • Lee JV; Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
  • Hinrichs JH; Department of Anatomy and.
  • Wagner PS; Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
  • Singh N; Department of Anatomy and.
  • Hein MY; Institute of Internal Medicine D, Medical Cell Biology, University Hospital Münster, Münster, Germany.
  • Borja M; Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • Detweiler AM; Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • Liu SY; Chan Zuckerberg Biohub SF, San Francisco, California, USA.
  • Nanjaraj A; Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria.
  • Sitarama V; Medical University of Vienna, Max Perutz Labs, Vienna, Austria.
  • Rugo HS; Chan Zuckerberg Biohub SF, San Francisco, California, USA.
  • Neff N; Chan Zuckerberg Biohub SF, San Francisco, California, USA.
  • Gartner ZJ; Department of Anatomy and.
  • Oliveira Pisco A; Department of Anatomy and.
  • Goga A; Department of Anatomy and.
  • Darmanis S; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.
  • Werb Z; Chan Zuckerberg Biohub SF, San Francisco, California, USA.
J Clin Invest ; 134(17)2024 Sep 03.
Article en En | MEDLINE | ID: mdl-39225101
ABSTRACT
Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Análisis de la Célula Individual / Transición Epitelial-Mesenquimal / Metástasis de la Neoplasia Límite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Análisis de la Célula Individual / Transición Epitelial-Mesenquimal / Metástasis de la Neoplasia Límite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos