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

Abstract

The molecular determinants of breast cancer (BC) pro-metastatic phenotype are largely unknown. Here, we leveraged lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during BC metastatization. We showed that metastases derive from rare pro-metastatic clones that are under-represented in primary tumors. Both low clonal-fitness and high metastatic-potential are independent of clonal origin. Differential expression and classification analyses revealed that the pro-metastatic phenotype is acquired in rare cells by concomitant hyper-activation of extracellular-matrix remodeling, dsRNA-interferon signaling, and stress-response pathways. Notably, genetic silencing of single pro-metastatic genes from different pathways significantly impairs migration in vitro and metastatization in vivo, with negligible effects on cell proliferation and tumor growth. In addition, gene-expression signatures from identified pro-metastatic genes predicts metastatic progression in BC patients, independently of known prognostic factors. This study elucidates previously unknown mechanisms of BC metastatization, and provides novel prognosis predictors and therapeutic targets for metastasis prevention.

Toward a systems-level probing of tumor clonality

“… 9 , 12 , 13 , 43 , 57 In metastasis, recent studies have integrated lineage tracing and computational algorithms in mouse models to quantitatively track properties of metastatic clones. 59 , 60 , 61 Similar to the findings reported in therapy resistance, pre-existing, heritable cell-intrinsic states predicted the metastatic potential of individual clones. 59 , 60 The clonal differences driving resistance and metastasis likely originate as a consequence of interplay between genetic alterations and non-genetic mechanisms, but the precise sequence of events remains to be elucidated.…”