Data from A Rare Subset of Primary Tumor Cells with Concomitant Hyperactivation of Extracellular Matrix Remodeling and dsRNA-IFN1 Signaling Metastasizes in Breast Cancer

Abstract

<div>Abstract<p>Metastatic breast cancer has a poor prognosis and is largely considered incurable. A better understanding of the molecular determinants of breast cancer metastasis could facilitate development of improved prevention and treatment strategies. We used lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during breast cancer metastasis and showed that metastases derive from rare prometastatic clones that are underrepresented in primary tumors. Both low clonal fitness and high metastatic potential were independent of clonal origin. Differential expression and classification analyses revealed that the prometastatic phenotype was acquired by rare cells characterized by the concomitant hyperactivation of extracellular matrix remodeling and dsRNA-IFN signaling pathways. Notably, genetic silencing of key genes in these pathways (KCNQ1OT1 or IFI6, respectively) significantly impaired migration <i>in vitro</i> and metastasis <i>in vivo</i>, with marginal effects on cell proliferation and tumor growth. Gene expression signatures derived from the identified prometastatic genes predict metastatic progression in patients with breast cancer, independently of known prognostic factors. This study elucidates previously unknown mechanisms of breast cancer metastasis and provides prognostic predictors and therapeutic targets for metastasis prevention.</p>Significance:<p>Transcriptional lineage tracing coupled with single-cell transcriptomics defined the transcriptional programs underlying metastatic progression in breast cancer, identifying prognostic signatures and prevention strategies.</p></div>

Implications of tumour heterogeneity on cancer evolution and therapy resistance: lessons from breast cancer

“…Enrichment of shared clonal lineages is observed across multiple metastatic sites, indicative of polyclonal seeding, with rare populations of cells also being able to seed metastasis [111]. Other studies, however, highlight dominance of a particular clone with largely non-overlapping lineages, suggestive of the ability of independent sub-clones in colonising distant sites [169][170][171]. Whilst these differences may in large be dependent on the models used in the different studies and the complexity of lineage tracing methodologies, it is becoming apparent that cells that are able to seed metastasis are pre-existing in primary TNBC and share phenotypic features that are selected for during the metastatic cascade (i.e.…”

“…Whilst these differences may in large be dependent on the models used in the different studies and the complexity of lineage tracing methodologies, it is becoming apparent that cells that are able to seed metastasis are pre-existing in primary TNBC and share phenotypic features that are selected for during the metastatic cascade (i.e. vascular mimicry [170] and/or selection of 'pro-metastatic' cells with distinct transcriptional signatures that can also predict patient outcome [169]). Of note, clonal tracking of cancer cells in the TNBC MMTV-PyMT mouse model across different stages of BC progression highlighted a substantial level of heterogeneity across various stages of breast carcinogenesis.…”