Abstract B39: PI3K therapy-induced adaptive mitochondria reprogramming fuels metastatic traits

Abstract

Abstract Tumors rewire cell metabolism and autophagy to adapt to environmental stress conditions, including hypoxia, starvation and oxidative stress. Such adaptive reprogramming includes a switch from oxidative phosphorylation to glycolysis, use of glutamine as fuel instead of glucose and increased biosynthesis of lipids and nucleotides. Although these processes promote resistance to apoptosis and support biomass expansion, they are also energetically inefficient, making it unclear how transformed cells accomplish highly energy-demanding tasks, including invasion and metastasis. Scattered evidences suggest that mitochondrial oxidative phosphorylation may be important for cancer traits, including stemmness, tumor repopulation and drug resistance. We recently demonstrated that targeting of the universal cancer node phosphatidylinositol-3 kinase (PI3K) induces extensive bioenergetics and transcriptional reprogramming in tumor cells, paradoxically culminating with preservation of homeostatic mitochondrial bioenergetics, opposing permeability transition and tumor cell death. Here we sought to understand how tumors adapt to molecular therapy as it pertains to tumor progression. Our results show that PI3K inhibitors used in the clinic induce global changes in activation of growth factor receptor kinases, reactivation of Akt and mTOR signaling, and dramatically increased tumor cell invasion. This involves the trafficking of energetically active mitochondria to the cortical cytoskeleton of tumor cells, supporting membrane lamellipodia dynamics, heightened turnover of focal adhesion complexes and increased velocity and distance of random cell migration. Furthermore, a single dose of PI3Ki increased liver metastasis after intrasplenic-injection of tumor cells in mice. Mechanistic studies pinpoint the role of Akt, mTOR, mitochondrial Hsp90s, the autophagy initiating complex ULK1/FIP200 and focal adhesion kinase (FAK) in the adaptive response to PI3Ki. Blocking oxidative phosphorylation by targeting mtHsp90s prevented the repositioning of mitochondria to sites of cell movements, impaired membrane dynamics and suppressed tumor cell invasion. Our results suggest a potential drawback for PI3K therapy, namely the increased risk of metastasis in patients. Targeting mitochondrial reprogramming is feasible, and could provide a novel therapeutic strategy to limit disease dissemination. Note: This abstract was not presented at the conference. Citation Format: M. Cecilia Caino, Dario C. Altieri. PI3K therapy-induced adaptive mitochondria reprogramming fuels metastatic traits. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B39.