Nada Kalaany, PhD

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

A main focus of our lab is to investigate the correlation between systemic metabolism and cancer incidence and progression, with the goal of identifying metabolic dependencies that could be targeted therapeutically in cancer patients.

Using models of lung, pancreatic and other tissue cancers, our lab aims at understanding:
How tumors survive and thrive in nutrient-limiting environments
How tumor growth and metabolism can be affected by the systemic metabolic state of the host (e.g. dietary restriction, obesity, insulin resistance)
How the host systemic metabolic state can, itself, get affected by tumor growth and metabolism (e.g. cancer-associated cachexia, or energy-wasting syndrome)

In our most recent work, we describe the identification of a unique metabolic dependency in pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with no effective therapies. We find that PDA relies on de novo ornithine synthesis (DNS) from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor 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 synthesis. We find that this dependence associates with arginine depletion in the PDA tumor 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.

Lab website