Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism

Abstract

Although cancer begins locally, symptoms associated with disease progression can be manifested systemically and be extremely debilitating for the patient. Identifying the genes that drive and mediate both local and systemic effects of tumorigenesis is important not only for developing treatments aimed at targeting cancer, but also for maintaining and improving patient quality of life. Here we use a multidisciplinary approach to uncover new mechanisms underlying Notch-PI3K/Akt-driven tumorigenesis in a well-established cancer paradigm in Drosophila melanogaster with highly predictive value (Palomero et al., 2007; Villegas et al., 2018). First, we designed an unbiased in vivo chemical screen to identify drugs that can selectively dampen this oncogenic cooperation without side effects. We identified a novel nitric oxide- dependent inflammatory pathway that is associated with Notch/Pten-dependent oncogenesis and perhaps amenable to pharmacological intervention.

On the other hand, phospho-proteomic analysis of these tumors revealed that aberrant PI3K/Akt signaling fuels Notch tumorigenesis in part by triggering mitochondrial dysfunction and generating oxidative stress. Our results also indicate that stress-activated Jnk signal might be restricting tumor progression by inducing apoptosis, and therefore acting as a tumor suppressor in this context.

Surprisingly, we found that Notch-PI3K/Akt tumors not only consume high amounts of glucose, but also remotely alter whole-body metabolism. High throughput large-scale and tissue-specific metabolomics revealed an unexpected interplay between the tumor and the host tryptophan-kynurenine metabolism, especially in the fat body, which ultimately leads to a systemic inflammation. Moreover, we detected changes related to tryptophan metabolism in the hemolymph, gut microbiota and brain of tumor- bearing hosts, further confirming for the first time that tumors can induce a multi-organ metabolic reprogramming. Consequently, diet supplementation with tryptophan was sufficient to prevent tumor formation through different multi-layered mechanisms. These findings could have important implications, since dietary interventions may hold the promise for the development of better treatments against cancer.