PTEN in cancer associated fibroblasts.

Decades of research have concluded that disruptions to Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) have profound effects on cancer progression. However, as our understanding of the tumor stroma has evolved, we can appreciate that disruptions to tumor suppressors such as PTEN should not be studied solely in an epithelial context. Inactivation of PTEN in the stroma is associated with worse outcomes in human cancers, therefore, it is important to understand activities regulated downstream of PTEN in stromal compartments. Studies reviewed herein provide evidence for important mechanistic targets downstream of PTEN signaling in cancer-associated fibroblasts (CAFs), a major component of the tumor stroma. We also discuss the potential clinical implications for these findings.

STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. Here, we show that disruption of the STAT3 signaling axis via genetic ablation of Stat3 in stromal fibroblasts in a Kras G12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immune-suppressive TME by decreasing M2 macrophages (F480+CD206+) and increasing CD8+ T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. In addition, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results provide a potential mechanism by which CAFs promote an immune-suppressive TME and promote tumor progression in a spontaneous model of PDAC.

PTEN in the Stroma.

Although tremendous progress has been made in understanding the functions of Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in tumor cells, only recently have tumor cell-non-autonomous PTEN actions within the tumor microenvironment (TME) been appreciated. While it is accepted that the TME actively communicates with cancer cells to influence disease progression, our understanding of the genes and pathways responsible is still evolving. Given that inactivation of PTEN in the stroma is correlated with worse outcomes in human cancers, determining the unique functions and mechanisms of PTEN regulation in various TME cell compartments is essential. In this review, the evidence for PTEN function in different TME cell compartments, the mechanisms governing PTEN inactivation, and the downstream pathways regulated by PTEN that are critical for intracellular communication, are covered. The potential clinical implications of these findings as well as the future directions for the study of stromal PTEN are discussed.