Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7
Yamamoto A, Huang Y, Krajina BA, McBirney M, Doak AE, Qu S, et al.
PNAS. 2023;120(10):e2214888120. DOI 10.1073/pnas.2214888120. PMID 36853945. PMCID PMC10013750.
How to cite
AMA
Yamamoto A, Huang Y, Krajina BA, McBirney M, Doak AE, Qu S, et al. Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7. Proc Natl Acad Sci U S A. 2023;120(10):e2214888120. doi:10.1073/pnas.2214888120APA
Yamamoto, A., Huang, Y., Krajina, B. A., McBirney, M., Doak, A. E., Qu, S., et al. (2023). Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7. Proceedings of the National Academy of Sciences, 120(10), e2214888120. https://doi.org/10.1073/pnas.2214888120BibTeX
@article{yamamoto2023metastasis,
title = {Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7},
author = {Yamamoto, A. and Huang, Y. and Krajina, B. A. and McBirney, M. and Doak, A. E. and Qu, S. and others},
journal = {Proceedings of the National Academy of Sciences},
volume = {120},
number = {10},
pages = {e2214888120},
year = {2023},
doi = {10.1073/pnas.2214888120},
pmid = {36853945}
}Aggressive tumors often die from the inside out, and that internal death, called necrosis, travels with a rising risk of metastasis. What has been hard to prove is whether the necrotic core actively drives cancer cells into the bloodstream or merely marks tumors that are dangerous for other reasons, because you cannot separate the two by comparing one patient to another.
Working in a rat transplantation model that detects disseminating cells roughly ten times more efficiently, the team caught a sharp low-to-high rise in circulating tumor cells that coincided with central necrosis, dilated vessels, and tumor emboli, and traced it to a tumor-secreted factor, angiopoietin-like 7. In a parallel cohort of metastatic breast cancer patients, longitudinal circulating-tumor-cell enumeration on a RareCyte assay confirmed that cell counts and clusters track with survival.
Key findings
- Longitudinal CTC monitoring stratified a real patient cohort. Across 102 blood samples from 40 metastatic breast cancer patients over 3 years, 73% (29 patients) had at least one circulating tumor cell and 13% (5 patients) had at least one CTC cluster.
- CTC burden was prognostic for survival. Patients with CTCs at the first blood draw, or CTC clusters at the first or second draw, had significantly worse overall survival, and 46 plasma proteins were enriched in high-CTC versus low-CTC samples.
- Angptl7 drives necrotic-core formation and dissemination. The tumor-secreted factor was enriched 32-fold in tumor versus host; knocking it down reduced necrotic-core area by 53 to 77% and cut single CTCs from an average of 181 to as few as 1 per animal.
RareCyte in the methods
“CTCs and CTC-clusters were enumerated in these fluid samples using a RareCyte assay”
— Yamamoto et al., PNAS (2023), Methods, “Human breast cancer patient samples”
Why it matters for RareCyte users
If you are considering a RareCyte workflow for circulating tumor cells, look at the job it was given here: the clinical arm of the study. The mechanistic work ran in a rat model, but the human evidence, the part that speaks to patients, rested on counting rare cells in blood. RareCyte supplied that readout. Whole blood was separated by density, all nucleated cells were deposited onto slides, and circulating tumor cells were scored by computer-assisted image analysis, without an antibody-capture enrichment step that can lose cells. That no-enrichment approach let the authors enumerate not just single CTCs but CTC clusters, longitudinally, across 40 patients and 102 draws. The result was prognostic: CTC presence and clusters tracked with worse overall survival. For your own studies the lesson is concrete. When you need a defensible cell count from a small clinical sample, a density-based, image-analysis CTC assay gives you both single cells and clusters from the same slide, and the numbers hold up against a hard endpoint like survival.
