The site of breast cancer metastases dictates their clonal composition and reversible transcriptomic profile

Abstract

Intratumoral heterogeneity is a driver of breast cancer progression, but the nature of the clonal interactive network involved in this process remains unclear. Here, we optimized the use of optical barcoding to visualize and characterize 31 cancer subclones in vivo. By mapping the clonal composition of thousands of metastases in two clinically relevant sites, the lungs and liver, we found that metastases were highly polyclonal in lungs but not in the liver. Furthermore, the transcriptome of the subclones varied according to their metastatic niche. We also identified a reversible niche-driven signature that was conserved in lung and liver metastases collected during patient autopsies. Among this signature, we found that the tumor necrosis factor–α pathway was up-regulated in lung compared to liver metastases, and inhibition of this pathway affected metastasis diversity. These results highlight that the cellular and molecular heterogeneity observed in metastases is largely dictated by the tumor microenvironment.

The breast cancer pro-metastatic phenotype requires concomitant hyper-activation of ECM remodeling and dsRNA-IFN1 signaling in rare clone cells

“…We found that metastases are almost monoclonal, with a single clone accounting for >90% cells. Our finding significantly differs from what reported in MDA-MB-231 cells using either genetic [20] or multicolor barcoding [56]. However, primary breast tumors were obtained in the former study by subcutaneous heterotopic transplantation, while in the latter the PT size at resection was much smaller (100 mm 3 vs 500-1000 mm 3 in our work) and polyclonal metastasis coexisted with monoclonal metastasis at other anatomical sites.…”

Modeling Colorectal Cancer Progression Reveals Niche-Dependent Clonal Selection

“…Our results demonstrate that clonal selection is niche-dependent, leading to speculations on the importance of individual TMEs selecting clones with the highest engraftment or seeding efficiency. Similar clonal selection was observed in breast cancer after transplantation of human fluorescently labelled cell lines into immune-deficient NSG mice [ 56 ]. In this study, lung metastases were polyclonal and liver metastases monoclonal.…”

“…To understand the clonal selection during CRC progression, we employed an optical labelling system that allows longitudinal tracing of individual clones at different sites. Similar to previous studies in mouse models of pancreatic cancer, breast cancer, and squamous cell carcinoma [ 56 , 57 , 58 ], we determined that clonal selection is a dominant event during cancer progression. Importantly, we demonstrate that clones, which expand under in vitro conditions, differ to in vivo selected clones.…”

Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer—A Review of Molecular Characterisation, Therapeutic Targets and Future Trends

“…The expected role of PD-L1 as a biomarker of response has not been proven in the early setting ( 138 , 139 ). Substantial differences between the clonal architecture and the microenvironment of primary and metastatic tumours ( 214 , 215 ) suggest that the role of a given biomarker should be evaluated separately in both early and advanced settings.…”