Medulloblastomas (MBs) remain the leading cause of death from solid cancers in children [30
]. These predominantly pediatric tumors of cerebellar origin present in infants, children, and to a lesser extent in the adult population. Concordantly, MBs are associated with aberrations in signaling cascades critical for brain development, organ patterning, and cell-fate determination like those controlled by the Wnt (WNT) or the hedgehog (HH) pathway. As high as 30 % of total human MBs bear evidence of aberrant hedgehog pathway activation. In this context, loss of function mutations in Patched (Ptch
) or activating mutations in Smoothened (Smo
), both trans-membrane proteins and essential components of Shh signaling, have been identified in human medulloblastomas [32
]. Mutations in cytoplasmic components of the hedgehog pathway such as Suppressor of Fused
) have also been described [42
]. Importantly, ectopic activation of Shh signaling [35
], constitutive activation of Smo itself [14
], or Ptch loss-of-heterozygosity [10
] are all sufficient, independently, to drive medulloblastoma formation in vivo. Consistently, global inhibition of the Shh pathway at the level of its receptors, while transiently beneficial in MB patients, remains confounded by a rapid development of drug resistance, a trait also conserved in hedgehog-associated tumor-bearing mice [50
]. Understanding the complexity of Shh signaling and the corresponding oncogenic network downstream of hedgehog is as such critical for developing effective and specific nodes for therapeutic manipulation.
In a recent study, we have demonstrated that hedgehog-driven MBs are distinguished by a dramatic accumulation of neutral lipids, underscoring these tumors’ metabolic, markedly lipogenic nature [2
]. Such lipogenic features are similar to those described in gliomas with EGF receptor mutations [11
] or a number of other human malignancies including cancer of the breast, lung, and prostate [25
]. Importantly, we demonstrated mechanistically that the effect of Shh on lipogenic metabolism proceeds through a multi-step program involving the inactivation of the tumor suppressor Rb and the induction of its negative target E2F1, a key transcriptional regulator of proliferation networks [16
]. Indeed, Shh-dependent induction of E2F1 promotes de novo lipid synthesis, induces the key enzyme Fatty Acid synthase (FASN), and primes the lipogenic machinery for a bioenergetics environment conducive to rapid proliferation. Impairing E2F activity and/or targeting de novo lipid synthesis with pharmacological means produced effective, reproducible therapeutic outcomes in MBs-bearing animals in vivo. These non-invasive approaches are especially promising for current MB treatments that damage the still-developing brain and result in catastrophic life-long side effects [31
]. It will be insightful to decipher the key components regulating the metabolic machinery, in particular, those promoting the acquisition of permissive substrate utilization patterns that fuel disease progression and enable malignant transformation.
It is widely established that adaptations to perceived stress conditions are hallmarks of proper functioning in systemic physiology. In fact, reciprocity in coordinated pathways of glucose and lipid metabolism and flexible metabolic shifts are common with dietary flux conditions including starvation, fasting or postprandial states [39
]. Such exquisite capacity for nutrient sensing is attributed, broadly speaking, to a complex web of signaling events. This includes (i) intracellular messengers like cAMP and associated kinases, (ii) mitochondrial enzymes responsive to acute changes in biochemical ratios such acetyl-CoA/CoA and NADH/NAD+ ratios, (iii) hormones that recruit specific substrate receptors like Glut4, and/or (iv) transcription factors that could alters metabolic patterns and substrate utilization at multiple, programmatic levels. A particular class of transcription factors with such capacity for reprogramming cellular responses and dictating nutrient sensing and signaling events are the fatty-acid activated peroxisome proliferator-activated receptors (PPARs). PPARs can elicit chronic, sustainable metabolic shifts through their transcriptional effects on metabolic enzyme gene expression. It is established that PPARγ activation confers significant benefit and ameliorate insulin sensitivity in vivo and ex vivo.
Here, we demonstrate the existence of a novel mechanism connecting Shh signaling to the PPARγ transcriptional machinery in neural precursors and in Shh-driven medulloblastoma. We show that Shh recruits the steroid nuclear receptor PPARγ, a key element in the nutrient sensing network, to reprogram cellular metabolism including the regulation of glycolysis proper. Indeed, Shh-dependent control of PPARγ dramatically activates the glycolytic modulators Glut4, hexokinase II (HKII) and pyruvate kinase M2 (PKM2), and promote glucose uptake in tumors in vivo. Importantly, the mechanism linking Shh to PPARγ and its aforementioned targets requires E2F1 in vivo and ex vivo.
In addition, this process is fully reversible with antagonizing PPARγ, an event that remarkably blunts tumor proliferation and extends survival of animals with medulloblastoma in vivo. In short, findings of this study provide critical insights into how vital and interlocked metabolic networks are altered or co-opted in Shh-driven MBs. The data also underscore the significant role of PPARγ downstream of Shh in dictating modes of substrate utilization and defining metabolic patterns in these tumors, and possibly other hedgehog-associated cancers. Given the fundamental role for PPARγ in nutrient sensing and the integration of dietary signals on the one hand and Shh functions in a myriad of biological activities like proliferation and self-renewal on the other hand, such link highlights the interplay between cell cycle regulators and the fuel processing machinery. Furthermore, these results are equally relevant to the pathophysiology of chronic diseases where glucose metabolism is dysregulated, particularly where sonic hedgehog activities are also implicated [21
]. Finally, considering the central role of the Rb-E2F complex in survival and proliferation and the widespread Rb pathway mutations found in human cancers, our findings could assist in better defining the etiology of tumor metabolism, in particular the perplexing phenotype of aerobic glycolysis and the lack of efficient mitochondrial oxidation of glucose despite the ostensible need for ATP in hyperproliferative cells. The requirement for E2F1 in Shh-regulated PPARγ dependent-glycolysis, as demonstrated, highlights its engagement in metabolic core fluxes and underscores the critical role for the Rb/E2F complex in metabolic reprogramming of medulloblastomas and their cells-of-origin.