PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity

Abstract

Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma.

YAP1 regulates PPARG and RXR alpha expression to affect the proliferation and differentiation of ovine preadipocyte

“…Previous investigation in mesenchymal stem cells has shown that TAZ negatively modulates adipogenesis by repressing PPARG . Therefore, the regulation of YAP1 on adipogenesis may be related to the activation of PPARG . IBMX is an inducer of adipogenesis that can elevate cyclic adenosine monophosphate (cAMP) content to activate PPARG expression.…”

“…In addition, the group of Guan demonstrated that YAP plays a crucial role in protein kinase A (PKA)‐induced adipocyte differentiation . Intriguingly, recent study in osteosarcoma cells and mice implanted with osteosarcoma cells found that PPARG agonists can reduce the nuclear localization of YAP1 and promote adipogenesis in the tumors . Similarly, knocking out Yap in osteoblast‐lineage cells suppresses cell proliferation and promotes adipocyte formation .…”

Targeting cancer stem cell pathways for cancer therapy

“…386 PPARγ activation also prevents cell spheroid formation and stem cell-like properties in bladder CSCs and induces adipocyte differentiation and β-catenin degradation in adipose tissues. 387 Furthermore, expression of PPARγ restrains YAP transcriptional activity to induce differentiation in osteosarcoma stem cells 388 and melanoma cells. 389 The PPARγ/NF-κB pathway promotes M2 polarization of macrophages to prevent cell death in ovarian CSCs 4.390 PPARγ activation promotes expression of its target gene PTEN to inhibit PI3K/Akt/ mTOR signaling, which stunts self-renewal, tumorigenicity, and metastasis in cervical CSCs, glioblastoma stem cells, and liver CSCs.…”

ROCK Inhibition Induces Terminal Adipocyte Differentiation and Suppresses Tumorigenesis in Chemoresistant Osteosarcoma Cells

“…It elicits terminal granulocytic differentiation in the leukemia cells by impairing transcriptional repression of genes necessary for differentiation (12). Differentiation therapy has the potential to be beneficial for cancer resistant to conventional agents, but limited evidence is available at present regarding its applicability to solid tumors (13,14). We have therefore now pursued the identification of a chemoresistant subpopulation of OSi cells and found that, in contrast to AX cells, AO cells are highly resistant to doxorubicin.…”