Abstract A46: 3D cultured prostate organoids derived from PTEN-conditional KO mouse models of prostate cancer reveal Class IA PI3Kα drives tumorigenesis and the levels of its lipid products are pH dependent
Authors: Sadiq Barzan A. 
Published: May 2018

Abstract
There are over a million new cases of prostate cancer annually in the world. In approximately 70% of the cases, at least one copy of the tumor suppressor gene, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is found to be lost at diagnosis. PTEN is a phosphatase that works in contrast of the class I PI3Ks (phosphoinositide 3-kinase). Class I PI3Ks are heterodimers composed of a catalytic subunit (p110α, p110β, p110δ, or p110γ), which lend their names to the different PI3K complexes, and a regulatory subunit (p85α, p85β, p84, or p101). These heterodimers are expressed differently and seem to assume specific roles in different cellular functions, both within different tissues and single cell types, and are able to convey spatially restricted signals, by phosphorylating the PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to produce PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate). These lipids belong to a complex signaling network widely implicated in human physiopathology. PI(3,4,5)P3 activates vital downstream proteins, namely Akt/PKB (protein kinase B), that are crucial for many cellular processes such as glucose metabolism, transcription, cell proliferation, cell migration, and apoptosis. The PI(3,4,5)P3 pool is controlled by the dephosphorylating abilities of PTEN, to produce PI(4,5)P2, and SHIP to produce PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), respectively. PI(3,4)P2 is an important second messenger itself that can also activate Akt. The loss of PTEN causes unregulated PI3K/Akt signaling, which allows survival of prostate cancer cells and prevents apoptosis.
We have made use of an established system to culture mouse prostate organoids from mouse models of prostate cancer. These mice have a site-specific deletion of the PTEN phosphatase gene. In these mouse models, deletion of PTEN leads to hyperplasic growth of epithelial cells, which at 6-8 weeks of age develops into prostate intraepithelial neoplasia, and eventually to adenocarcinoma by 4 months. Therefore, they are good cancer models of the prostate gland and thus present a good opportunity to study the mechanisms of the prostate cancer. PTEN-dKO tissue and organoids show a significant reduction in PTEN protein expression in the mouse prostate, and grow to a more condensed yet sizable cell mass, in comparison to the wild-type controls. We have used this model to dissect class I PI3K signaling isoform specificity in driving tumorigenesis in mice prostate cancer, as well inferring the levels of the PI(3,4,5)P3 and PI(3,4)P2 to establish a route in which these lipids play a role in the development and survival of prostatic cancerous cells. Our data indicate that there is a substantial increase in the accumulated levels of PI(3,4,5)P3 and PI(3,4)P2. We show that this is primarily driven by the class IA PI3Kα isoform. We further report that the levels of those two vital signaling lipids are dependent on the pH level of the tumor microenvironment. Furthermore, the vast accumulation of PI(3,4)P2 seen in the PTEN-dKO mouse prostate tissue and organoids suggest that PTEN may also be the primary phosphatase dephosphorylating the PI(3,4)P2 lipids. Our findings using the organoid system that are derived from mouse models of prostate cancer further our knowledge in understanding the mechanisms of this diseases to allow finding suitable targeted treatments for it.
Note: This abstract was not presented at the conference.
Citation Format: Barzan A. Sadiq. 3D cultured prostate organoids derived from PTEN-conditional KO mouse models of prostate cancer reveal Class IA PI3Kα drives tumorigenesis and the levels of its lipid products are pH dependent [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A46.