PI3Kδ activity controls plasticity and discriminates between EMT and stemness based on distinct TGFβ signaling

Abstract

The stem cells involved in formation of the complex human body are epithelial cells that undergo apicobasal polarization and form a hollow lumen. Epithelial plasticity manifests as epithelial to mesenchymal transition (EMT), a process by which epithelial cells switch their polarity and epithelial features to adopt a mesenchymal phenotype. The connection between the EMT program and acquisition of stemness is now supported by a substantial number of reports, although what discriminates these two processes remains largely elusive. In this study, based on 3D organoid culture of hepatocellular carcinoma (HCC)-derived cell lines and AAV8-based protein overexpression in the mouse liver, we show that activity modulation of isoform δ of phosphoinositide 3-kinase (PI3Kδ) controls differentiation and discriminates between stemness and EMT by regulating the transforming growth factor β (TGFβ) signaling. This study provides an important tool to control epithelial cell fate and represents a step forward in understanding the development of aggressive carcinoma.

Intrinsic cancer cell phosphoinositide 3‐kinase δ regulates fibrosis and vascular development in cholangiocarcinoma

“…TGFβ overexpression leads to CCA tumorigenesis and metastasis 41 . Furthermore our recent work demonstrated that PI3Kδ activity discriminates EMT and stemness based on distinct TGFβ signalling in malignant hepatocytes 30 . Interestingly in this study our results showed that PI3Kδ expression in CCA cells increased TGFβ expression both in vitro 3D cultures and in vivo.…”

“…41 Furthermore our recent work demonstrated that PI3Kδ activity discriminates EMT and stemness based on distinct TGFβ signalling in malignant hepatocytes. 30 Interestingly in this study our results showed that PI3Kδ expression in CCA cells increased TGFβ expression both in vitro 3D cultures and in vivo. Particularly PI3Kδ expression in CCA cells promoted secretion of TGFβ and angiogenic factors such as VEGF and bFGF in the serum of xenograft mice (Figure 5).…”

“…Mouse PI3Kδ expression in the liver was achieved by AAV gene transfer plasmids pAAV TBG m PI3Kδ (VB180205-1022wdw, Vector Builder) according to the previous study. 30 8-week-old C57BL/6 mice (purchased from Charles River) were injected in the tail vein using pAAV TGB m PI3Kδ and pAAV TBG EGFP adenovirus (10 11 particules/mouse). Eight weeks later, mice were sacrificed.…”

Non-coding mutations at enhancer clusters contribute to pancreatic ductal adenocarcinoma

“…TGF-β regulates MIR100HG transcription and thus the release of its hosted miRs, inducing EMT, encouraging cell motility and metastasis 25 . Here, we identi ed many TGF-β related genes such as FGF1 76 , KDM6B 77 , LIF 78 , PIK3CD 79 , PXDC1 and TAGLN 80 were signi cantly downregulated in the two CRISPRi groups compared to the control (Extended Data Fig. 9).…”

Opportunities and challenges of hepatocellular carcinoma organoids for targeted drugs sensitivity screening

“…And in 2015, the adult liver organoid model capable of long-term stable expansion in vitro was established. The need for disease research has led to the development of organoid models of liver cancer to study the initiation and progression of liver cancer with progressive applications in cancer development mechanisms (11)(12)(13)(14)(15)(16), preclinical research (17), personalized medicine (18)(19)(20)(21) and drug screening (22,23). Many factors can induce the oncogenesis of the liver cancer, organoid can also be help to study the mechanism of oncogenesis and development of HCC.…”