CNS metastasis-associated stromal cells

Metastasis to the central nervous system (CNS) remains a clinically vexing complication and a major cause of mortality and morbidity in patients with systemic cancer. However, the mechanistic interactions of the neural niche with disseminated tumors cells in CNS metastases (CM) are still poorly understood. In this study, aimed at better understanding the pathophysiologic cross-talk between the neural niche and secondary metastatic tumors, we generated five different patient-derived cell lines (PDCs) originating from surgically resected CM: two lung adenocarcinomas to brain (CM03, CM08), one lung adenocarcinoma to spine (CM02), one small cell lung carcinoma (SCLC) to brain (CM04), and one breast carcinoma to brain (CM01). To assess the genetic and epigenetic characteristics of each PDC, DNA and RNA sequencing, and DNA methylation analysis was performed. CM01, CM02, CM03, and CM08-PDCs revealed normal copy number profiles and retention of germline mutations with the same allelic ratios as seen in patient-matched germline DNA from blood. In contrast, CM04-PDC resembled its patient tumor, showing numerous copy number and somatic alterations. RNA-seq and DNA methylation analysis demonstrated that non-tumor PDCs highly resembled each other, suggesting a common cell of origin for these cells. In addition, non-tumor PDCs revealed gene expression signatures associated with cancer associated fibroblasts, epithelial to mesenchymal transition, and mesenchymal stem cells. Further in vivo studies demonstrated that CM04 cells were tumorigenic, whereas CM08 cells were unable to form tumors in mice. However, CM04:CM08 mixed tumors were significantly smaller than CM04 only tumors. Immunohistochemistry revealed induction of a fibrotic response in CM04:CM08 mixed tumors only; this was also seen in vitro, where only CM01, CM02, CM03, CM08-PDCs displayed evidence of extensive collagen and fibronectin deposition. These data offer the first evidence that CNS metastasis-associated stromal cells (cMASCs) produce a collagen and fibronectin-rich extracellular matrix to constitute a protective barrier by the host, impeding growth of tumor cells, suggesting that the therapeutic potential of these cells need to be further explored