|Title||Genetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Bastos DC, Ribeiro CF, Ahearn T, Nascimento J, Pakula H, Clohessy J, Mucci L, Roberts T, Zanata SM, Zadra G, Loda M|
|Date Published||2021 03|
|Keywords||Adult, Aged, Aged, 80 and over, Animals, Cell Movement, Fatty Acid Synthase, Type I, Humans, Lipogenesis, Male, Mice, Mice, Knockout, Middle Aged, Neoplasm Invasiveness, Prostatic Neoplasms, PTEN Phosphohydrolase|
Loss of the tumor suppressor gene Pten in murine prostate recapitulates human carcinogenesis and causes stromal proliferation surrounding murine prostate intraepithelial neoplasia (mPIN), which is reactive to microinvasion. In turn, invasion has been shown to be regulated in part by de novo fatty acid synthesis in prostate cancer. We therefore investigated the effects of genetic ablation of Fasn on invasive potential in prostate-specific Pten knockout mice. Combined genetic ablation of Fasn and Pten reduced the weight and volume of all the prostate lobes when compared to single knockouts. The stromal reaction to microinvasion and the cell proliferation that typically occurs in Pten knockout were largely abolished by Fasn knockout. To verify that Fasn knockout indeed results in decreased invasive potential, we show that genetic ablation and pharmacologic inhibition of FASN in prostate cancer cells significantly inhibit cellular motility and invasion. Finally, combined loss of PTEN with FASN overexpression was associated with lethality as assessed in 660 prostate cancer patients with 14.2 years of median follow-up. Taken together, these findings show that de novo lipogenesis contributes to the aggressive phenotype induced by Pten loss in murine prostate and targeting Fasn may reduce the invasive potential of prostate cancer driven by Pten loss. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
|Alternate Journal||J Pathol|
|PubMed Central ID||PMC7898611|
|Grant List||R01 CA187918 / CA / NCI NIH HHS / United States |
U01 CA167552 / CA / NCI NIH HHS / United States
R01 CA131945 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
Massimo Loda, M.D.