Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells.
Bottom Line: To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing.Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness.The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.
Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.Show MeSH
Related in: MedlinePlus
Mentions: Together, our observations include the following. (1) CTC expression profiles cluster into three classes, including a major “classical CTC” group, and others that are defined by platelet-derived markers or proliferative signatures. (2) Common features shared by virtually all classical CTCs include expression of both epithelial and mesenchymal markers, the stem cell-associated gene Aldh1a2, and three highly expressed transcripts, Klf4, Igfbp5, and Dcn. The specific localization of Igfbp5-expressing cells at the epithelial-stromal boundary within primary tumors may point to a region that contributes significantly to CTC generation. (3) The most highly enriched CTC-specific transcripts shared by almost all classical CTCs encode extracellular matrix proteins, such as Sparc. (4) Aberrant expression in CTCs of this ECM gene product, which is normally abundant in the tumor stromal compartment, is observed in both mouse and human pancreatic CTCs, and its knockdown attenuates cancer cell migration and invasion in reconstituted systems. (Figure 7)
Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.