Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes

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 exp...

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Published in:	The Journal of clinical investigation Vol. 134; no. 17; pp. 1 - 14
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-09-2024
Subjects:	Adaptation Adaptation (Physiology) Animals Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cancer cells Cell culture Cell Line, Tumor Cells Cellular stress response Clinical outcomes Epithelial cells Epithelial-Mesenchymal Transition Female Gene expression Gene Expression Regulation, Neoplastic Genes Genetic transcription Health aspects Humans Lungs Medical research Medicine, Experimental Metastases Metastasis Mice Motility Neoplasm Metastasis Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Oncology, Experimental Patient outcomes Patients Physiological aspects Plasticity Single-Cell Analysis Stem cells Therapeutic targets Transcriptome Transcriptomes Tumors Canada Austria California United States Oncology Bioinformatics Breast cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: ZW is deceased.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI164227