Nada Kalaany, PhD

Institution: Children's Hospital
Research: Effects of systemic metabolic alterations on cancer growth
Grants & Publications: Harvard Catalyst
Categories: Children's

The broad interest of the Kalaany lab is to define the role of systemic metabolism in cancer initiation and progression using a combination of genetics, in vivo transplant models, cell biology and metabolic approaches. Our studies are focused on identifying metabolic vulnerabilities in cancers growing under distinct systemic metabolic states, including obesity, insulin resistance, dietary restriction, and cachexia. Current ongoing projects in the lab:

Role of insulin/IGF-1 signaling in Kras-driven lung cancer. Our lab addressed a long-standing question in KRAS-driven lung cancer and identified a metabolic vulnerability that could be exploited therapeutically using drugs available in the clinic. Although KRAS direct binding to and activation of PI3K had been known to be required for KRAS-driven lung cancer formation, the contribution of insulin receptor (IR) and IGF-1 receptor (IGF1R), in the context of mutant KRAS, had remained largely controversial. We provided robust genetic evidence that lung-specific dual ablation of insulin receptor substrates (IRS1/IRS2), which mediate insulin and IGF-1 signaling, strongly suppresses lung tumor initiation in a mouse model with KRAS activation and p53 loss. We also showed that inhibition of IR/IGF1R in KRAS-mutant human non-small cell lung cancer (NSCLC) cells decreases the uptake of amino acids, generating a metabolic dependency on protein degradation processes, including autophagy and the proteasome. (Published in Proc Natl Acad Sci USA PMCID: PMC5910837). We are currently investigating the role of insulin/IGF-1 signaling in KRAS-driven lung cancer- associated body wasting or cachexia.

Nitrogen metabolism as a dependency in obesity-associated pancreatic cancer. Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA); yet the metabolic dependencies of obesity-associated PDA have remained largely unexplored. We showed that similar to AKT-activated PDA, obesity-driven PDA exhibits increased growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. Specifically, we found that the mitochondrial, extrahepatic form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced. This induction is accompanied by enhanced nitrogen flux into the urea cycle and is required for PDA growth. Analysis of resected tumors from PDA patients indicated that ARG2 levels correlate with body mass index (BMI) or with activated AKT independent of BMI. The specific dependency of PDA on ARG2, which unlike ARG1 is not associated with human diseases, opens a new therapeutic window for the treatment of pancreatic cancer in overweight patients as well as lean patients carrying tumors with AKT- activating mutations, independent of obesity (Published in Nat Commun PMCID: PMC5556090). We are currently investigating the role of another nitrogen-dependent pathway, i.e. polyamine biosynthesis, in pancreatic cancer progression.

Adaptation of pancreatic cancer cells to nutrient deprivation. In this work, we selected for clonal human pancreatic ductal adenocarcinoma (PDA) cells that survive and adapt to limiting levels of both glucose and glutamine. We found that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones use amino acids 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. (Published in Proc Natl Acad Sci USA PMCID: PMC7958225, available 09/02/2021). We are currently exploring the epigenetic basis of the regulation of pancreatic cancer cell adaptation to nutrient deprivation.