Genome‐wide RNA‐Seq identifies Fas/FasL‐mediated tumoricidal activity of embryonic stem cells

The discovery of tumor tropism of stem cells revealed the intimate relationship between stem cells and tumor cells, but the functional role of stem cells in tumorigenesis is poorly understood. To investigate embryonic stem cell (ESC) and tumor cell interactions, we co‐cultured mouse ESCs with mouse melanoma B16‐F10 cells or mouse pancreatic tumor Pan02 cells, and found that ESCs significantly inhibited tumor cell proliferation. Coculture of ESCs and tumor cells resulted in significant inhibition of tumorigenesis in vivo. Histological analyses indicated that ESCs encircled apoptotic tumor cells. We carried out time course RNA‐Seq analyses of ESC and tumor cell co‐cultures, and identified Fas/FasL signaling as a major pathway involved in ESC‐mediated apoptosis of tumor cells. We further generated FADD‐deficient tumor cells by CRISPR/Cas9‐mediated gene editing, and demonstrated that FADD‐deficient tumor cells were obviously resistant to ESC‐mediated inhibition of tumor cell proliferation. Our results indicate the Fas/FasL signaling pathway plays a critical role in ESCs‐mediated tumoricidal activity. What's new? Stem cells engage in complex activities in the tumor milieu, including tumor tropism, a property potentially leveraged to aid the delivery of therapeutic agents to tumors. Here, embryonic stem cells (ESCs) from mice were investigated to better understand tumor‐stem cell interactions. In vitro, ESCs were found to inhibit tumorigenesis when co‐cultured with tumor cells. In vivo, simultaneous injection of tumor cells and ESCs resulted in reduced tumor cell lethality and reduced tumor growth. Genome‐wide RNA sequencing identified Fas/FasL signaling as a mediator of ESC tumoricidal activity, while deletion of Fas‐associated protein with death domain (FADD) produced resistance to ESC‐mediated apoptosis.