Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1.

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.

Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis.

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.

Bullying Victimization and Perpetration Among Adolescent Sport Teammates.

PURPOSE: Bullying is a specific pattern of repeated victimization explored with great frequency in school-based literature, but receiving little attention within sport. The current study explored the prevalence of bullying in sport, and examined whether bullying experiences were associated with perceptions about relationships with peers and coaches. METHOD: Adolescent sport team members (n = 359, 64% female) with an average age of 14.47 years (SD = 1.34) completed a pen-and-paper or online questionnaire assessing how frequently they perpetrated or were victimized by bullying during school and sport generally, as well as recent experiences with 16 bullying behaviors on their sport team. Participants also reported on relationships with their coach and teammates. RESULTS: Bullying was less prevalent in sport compared with school, and occurred at a relatively low frequency overall. However, by identifying participants who reported experiencing one or more act of bullying on their team recently, results revealed that those victimized through bullying reported weaker connections with peers, whereas those perpetrating bullying only reported weaker coach relationships. CONCLUSION: With the underlying message that bullying may occur in adolescent sport through negative teammate interactions, sport researchers should build upon these findings to develop approaches to mitigate peer victimization in sport.

A proposed theoretical model to explain relative age effects in sport.

Exemplary scientific methods describe concepts and provide theories for further testing. For the field of relative age effects (RAEs) in sport, the scientific method appears to be limited to description. The purpose of this paper is to provide a theoretical model to explain RAEs in sport, which researchers can use to test the effects, as well as to generate new hypotheses and recommendations. Herein, we argue that social agents have the largest influence on RAEs. Specifically, we propose that parents influence RAEs through Matthew effects, coaches influence RAEs through Pygmalion effects and athletes influence RAEs through Galatea effects. Integrating these three theories, we propose a model that explains RAEs through these various social agents. This paper provides a theoretical foundation from which researchers can further understand, explain and eventually use to create policies aimed at limiting the negative effect of relative age in sport.