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 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.
Authors
- Marco Y. Hein (ORCID: https://orcid.org/0000-0002-9490-2261)
- Aamna Abbasi
- Angela M. Detweiler (ORCID: https://orcid.org/0000-0001-7026-5467)
- Joyce V. Lee (ORCID: https://orcid.org/0000-0003-2620-555X)
- Ankitha Nanjaraj
- Elena Atamaniuc
- Saad Hasnain (ORCID: https://orcid.org/0000-0001-8464-5129)
- Namrata Singh (ORCID: https://orcid.org/0000-0002-8912-2949)
- Spyros Darmanis (ORCID: https://orcid.org/0000-0003-4002-8158)
- Su-Yang Liu
- Sophia Durney (ORCID: https://orcid.org/0000-0003-4217-5741)
- Weilun Tan
- Zena Werb (ORCID: https://orcid.org/0000-0002-6525-3872)
- Christopher S. McGinnis (ORCID: https://orcid.org/0000-0001-6923-9341)
- Catherine M.M. Diadhiou (ORCID: https://orcid.org/0000-0003-3389-5886)
- Zev J. Gartner (ORCID: https://orcid.org/0000-0001-7803-1219)
- Michael Borja (ORCID: https://orcid.org/0009-0006-4527-3370)
- Johanna H. Hinrichs
- Andrei Goga (ORCID: https://orcid.org/0000-0001-9127-0986)
- Norma Neff (ORCID: https://orcid.org/0000-0001-7141-5420)
- Daphne Superville (ORCID: https://orcid.org/0000-0002-8317-8431)
- Leena Awni
- Vaishnavi Sitarama
- Angela Oliveira Pisco (ORCID: https://orcid.org/0000-0003-0142-2355)
- Hope S. Rugo (ORCID: https://orcid.org/0000-0001-6710-4814)
- Juliane Winkler (ORCID: https://orcid.org/0000-0002-9762-1721)
- Patrick S Wagner
Institutions
- University of California, San Francisco (US)
- Max Perutz Labs (AT)
- Comprehensive Cancer Center Vienna (AT)
- University Hospital Münster (DE)
- Chan Zuckerberg Initiative (United States) (US)
- Vienna Biocenter (AT)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1172/jci164227
- Citations
- 17
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 4.80
Funders
- Breast Cancer Research Foundation
- Vienna Science and Technology Fund
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute
- Congressionally Directed Medical Research Programs