PPM1A the Guardian of Homeostasis in the Microenvironment: PPM1A Deficiency in SKPs Affects Function and Fate of Immune and Endothelial Cells in the Tumor Microenvironment

Using Protein phosphatase metal dependent 1 A (PPM1A) knockout mice, created in our laboratory, we identified PPM1A as a major regulator of the microenvironment, down regulating the inflammation response (Dvashi et al, 2014). In the PPM1A-ablated mice, wound-healing process goes awry and culminates in uncontrolled inflammation and angiogenesis. As these features are comprised among the Hallmarks of Cancer, reflecting the microenvironment response to tumor cells’ growth, we investigated the role of PPM1A in cancer using multiple mouse models. Surprisingly, we found that the absence of PPM1A could be either tumor promoting or tumor suppressive depending on the tumor initiation protocol.

When cultured in non-adherent conditions and with specific growth factors, primary dermal fibroblasts generate three-dimensional sphere of skin-derived precursor cells (SKPs). These cells are characterized by their capacity for self-renewal, pluripotency and expression of specific SKP markers. We generated 3D-spheres from dermal fibroblasts of wild-type (WT) and PPM1A-ablated (KO) mice, and functionally proved they have SKP properties. Interestingly, PPM1A-KO SKPs showed differences in gene expression as well as physical and functional properties compared to WT cells. A bioinformatics analysis of the gene expression in PPM1A-KO SKPs predicts a significant role in affecting, via aberrant functions and signaling processes, tumor microenvironment – be it directly or indirectly, by affecting surrounding cells such as endothelial cells and immune cells.

Here we will demonstrate the effects of PPM1A-ablation on SKP functionality and their signaling effect. Using conditioned-medium we will demonstrate SKP effects on endothelial cells functionality, hematopoietic stem cell differentiation and immune cells activation. We will argue that PPM1A activity in SKPs is crucial for maintaining homeostasis of the microenvironment in response to pathology and tumor development.