Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320

Abstract

Phosphatase and tensin homolog deleted on chromosome ten (Pten) in stromal fibroblasts suppresses epithelial mammary tumors, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2, are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumor angiogenesis and tumor cell invasion. Expression of the Pten-miR-320-Ets2 regulated secretome distinguished human normal breast stroma from tumor stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumor suppressor axis that acts in stromal fibroblasts to reprogram the tumor microenvironment and curtail tumor progression.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…We found that factors secreted from lung adenocarcinoma cells can induce ZEB1 mRNA, repress Pten mRNA and trigger fibroblast proliferation, suggesting a mechanism through which this pattern can be transferred from tumour cells to adjacent fibroblasts. Mutation of Pten in the tumour stroma is sufficient to facilitate breast cancer initiation 33,42 , implying an important function for downregulation of Pten in tumour-associated fibroblasts. Indeed, it has been demonstrated recently that Pten can be secreted and taken up by adjacent cells 43 , raising the possibility that elimination of Pten in fibroblasts is necessary to remove a secondary source of secreted Pten that would otherwise be taken up by adjacent tumour cells.…”

Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment

“…4E). Interestingly, all these miRNAs have been reported in the context of tumor progression, [26][27][28][29] although their role in the regulation of immune cell functions is not known.…”

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

“…A major mechanism of PTEN-mediated tumor suppression has been attributed to its function as a lipid phosphatase inhibitor of the PI3K/AKT pathway; however, PTEN has proven to be a complex regulator of cellular homeostasis with both lipid phosphatasedependent and -independent roles in proliferation, senescence, motility, and chromosomal stability (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Recently, PTEN has also emerged as an important regulator of immune function.…”