Collective Invasion in Breast Cancer Requires a Conserved Basal Epithelial Program

By Kevin J. Cheung, E. Gabrielson, Zena Werb, Andrew J. Ewald. Cell, 2013

779 citations recorded by the source corpus.

SUMMARY Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/03c1cd33e42a70e7da038cb5814fec336487fb75

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Citations in the corpus

A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion (2017, background): “Clustering of α(5)β(1) integrins determines adhesion strength whereas α(v)β(3) and talin enable mechanotransduction.”
Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters (2016, background): “In breast cancer, collective invasion is facilitated by invasive leader cells, a subpopulation of tumor cells that highly express keratin 14 (K14) and other basal epithelial markers (11).”
The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “The tumor invasive front is a likely site for selection of metastatic traits (Cheung et al., 2013).”
EMT subtype influences epithelial plasticity and mode of cell migration (2018, background): “The P-EMT program may thus confer tumor cells with invasive properties while simultaneously allowing them to retain intercellular cohesions that facilitate collective behavior (Cheung et al., 2013; Lambert et al., 2017; Liu et al., 2014b; Puram et al., 2017; Revenu and Gilmour, 2009; Westcott et al.”
Systems Biology of Cancer Metastasis (2019, methodology): “Work using organoid cultures of primary breast cancer epithelial cells has shown that during collective epithelial cell migration, the leading cell remains positive for the basal epithelial marker cytokeratin 14 (K14)(Cheung et al., 2013).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “large populations of followers to which they remain attached via cell-cell junctions (Cheung et al., 2013).”
Distinct EMT programs control normal mammary stem cells and tumour-initiating cells (2015, neutral): “We dissociated adenocarcinomas into tumour organoids as previously described 13 .”