PI3Kδ activity controls 1 plasticity and discriminates between EMT and stemness based on distinct TGF signalling

[en] 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  (TGF) signalling. Thus, providing an important tool to control epithelial cell fate and represents a step forward in understanding the development of aggressive carcinoma.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Agnetti, Jean ^✱

Vanessa Bou Malham ^✱

Christophe Desterke ^✱

Nassima Benzoubir

Juan Peng Wang

Sophie Jacques

Rahmouni, Souad ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics

Di Valentin, Emmanuel ; Université de Liège - ULiège > Département des sciences de la vie > Virologie - Immunologie ; Université de Liège - ULiège > GIGA > GIGA Platform Viral vectors

Tuan Zea Tan

Didier Samuel

Jean Paul Thiery

Ama Gassama-Diagne

^✱ These authors have contributed equally to this work.

Language :

English

Title :

PI3Kδ activity controls 1 plasticity and discriminates between EMT and stemness based on distinct TGF signalling

Publication date :

2022

Journal title :

Communications Biology

eISSN :

2399-3642

Publisher :

Springer Nature

Volume :

Pages :

740

Peer reviewed :

Peer Reviewed verified by ORBi

Data Set :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314410/

Available on ORBi :

since 27 June 2022

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Bibliography

Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).
Bilanges, B., Posor, Y. & Vanhaesebroeck, B. PI3K isoforms in cell signalling and vesicle trafficking. Nat. Rev. Mol. Cell Biol. 20, 515–534 (2019).
Guillermet-Guibert, J. et al. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc. Natl Acad. Sci. USA 105, 8292–8297 (2008).
Chantry, D. et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J. Biol. Chem. 272, 19236–19241 (1997).
Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).
Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).
Goulielmaki, E. et al. Pharmacological inactivation of the PI3K p110δ prevents breast tumour progression by targeting cancer cells and macrophages. Cell Death Dis. 9, 678 (2018).
Ko, E. et al. PI3Kδ is a therapeutic target in hepatocellular carcinoma. Hepatology 10.1002/hep.30307 (2018).
Park, G. B. & Kim, D. Insulin-like growth factor-1 activates different catalytic subunits p110 of PI3K in a cell-type-dependent manner to induce lipogenesis-dependent epithelial-mesenchymal transition through the regulation of ADAM10 and ADAM17. Mol. Cell. Biochem. 439, 199–211 (2018).
Sawyer, C. et al. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110δ. Cancer Res. 63, 1667–1675 (2003).
Yue, D. & Sun, X. Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma. Cell Death Dis. 9, 1–11 (2018).
Peng, J. et al. Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization. Nat. Commun. 6, 5937 (2015).
Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017).
Pradella, D., Naro, C., Sette, C. & Ghigna, C. EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol. Cancer 16, 8 (2017).
Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).
Pei, D., Shu, X., Gassama-Diagne, A. & Thiery, J. P. Mesenchymal–epithelial transition in development and reprogramming. Nat. Cell Biol. 21, 44–53 (2019).
Hepburn, A. C. et al. Correction: The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance. Oncogene 38, 4425 (2019).
Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).
Lohmann, V. et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 110–113 (1999).
Macleod, K. F. et al. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 9, 935–944 (1995).
Guerra, M. T. & Nathanson, M. H. Calcium signaling and secretion in cholangiocytes. Pancreatology 15, S44–S48 (2015).
Christodoulou, N. et al. Sequential formation and resolution of multiple rosettes drive embryo remodelling after implantation. Nat. Cell Biol. 20, 1278–1289 (2018).
Shahbazi, M. N. et al. Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. Nature 552, 239–243 (2017).
Taniguchi, K. et al. Lumen formation is an intrinsic property of isolated human pluripotent stem cells. Stem Cell Rep. 5, 954–962 (2015).
Schindler, M. et al. Agarose microgel culture delineates lumenogenesis in naive and primed human pluripotent stem cells. Stem Cell Rep. 16, 1347–1362 (2021).
Yamashita, T. et al. EpCAM and α-fetoprotein expression defines novel prognostic subtypes of Hepatocellular Carcinoma. Cancer Res. 68, 1451–1461 (2008).
Nio, K., Yamashita, T. & Kaneko, S. The evolving concept of liver cancer stem cells. Mol. Cancer 16, 4 (2017).
Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572–579 (2012).
Bilder, D., Schober, M. & Perrimon, N. Integrated activity of PDZ protein complexes regulates epithelial polarity. Nat. Cell Biol. 5, 53–58 (2003).
Bryant, D. M. & Mostov, K. E. From cells to organs: building polarized tissue. Nat. Rev. Mol. Cell Biol. 9, 887–901 (2008).
Sharov, A. A. et al. Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. BMC Genomics 9, 269 (2008).
Zhang, J. et al. A Human iPSC model of hutchinson gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011).
Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat. Cell Biol. 13, 541–549 (2011).
Li, Q. et al. A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes. Nat. Commun. 8, 15166 (2017).
Ramazani, Y. et al. Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol. 68–69, 44–66 (2018).
Martino, F., Perestrelo, A. R., Vinarský, V., Pagliari, S. & Forte, G. Cellular mechanotransduction: from tension to function. Front. Physiol. 9, 824 (2018).
Nakai, H. et al. Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J. Virol. 79, 214–224 (2005).
Yan, Z., Yan, H. & Ou, H. Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. Gene 506, 289–294 (2012).
Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605–618 (2014).
Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27, 719–724 (2013).
Chaudhuri, P., Smith, A. H., Putta, P., Graham, L. M. & Rosenbaum, M. A. P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization. Am.J. Physiol. Cell Physiol. https://doi.org/10.1152/ajpcell.00425.2020 (2021).
Acevedo, L. G., Bieda, M., Green, R. & Farnham, P. J. Analysis of the mechanisms mediating tumor-specific changes in gene expression in human liver tumors. Cancer Res. 68, 2641–2651 (2008).
Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).
Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12, 410–416 (2006).
Burute, M. et al. Polarity reversal by centrosome repositioning primes cell scattering during epithelial-to-mesenchymal transition. Developmental Cell 40, 168–184 (2017).
Xu, J., Lamouille, S. & Derynck, R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).
Roberts, A. B. et al. Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev. 17, 19–27 (2006).
Dooley, S. et al. Hepatocyte-Specific Smad7 expression attenuates TGF-β–mediated fibrogenesis and protects against liver damage. Gastroenterology 135, 642–659.e46 (2008).
Yu, Y. et al. Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-β signaling. PNAS 114, 10113–10118 (2017).
Dennler, S. et al. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 17, 3091–3100 (1998).
Gripon, P. et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc. Natl Acad. Sci. USA 99, 15655–15660 (2002).
Pastushenko, I. & Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29, 212–226 (2019).
Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).
Varga, J. & Greten, F. R. Cell plasticity in epithelial homeostasis and tumorigenesis. Nat. Cell Biol. 19, 1133–1141 (2017).
Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).
Madsen, R. R. PI3K in stemness regulation: from development to cancer. Biochem Soc. Trans. 48, 301–315 (2020).
Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003).
Breitling, R., Armengaud, P., Amtmann, A. & Herzyk, P. Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett. 573, 83–92 (2004).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Cline, M. S. et al. Integration of biological networks and gene expression data using Cytoscape. Nat. Protoc. 2, 2366–2382 (2007).