About

Peter J Mullen, Ph.D., is an Assistant Professor of Microbiology and Immunology at the Keck School of Medicine of USC, with a secondary appointment in the Leonard Davis School of Gerontology at USC. He has spent over 10 years studying the regulation and role of metabolism in tumor growth and viral infections. His research focuses on understanding how whole-body metabolism influences respiratory virus replication, cancer progression, and aging. The goal of his recently established lab is to elucidate specific nutrient requirements to develop novel strategies that reduce disease and increase lifespan. His work includes investigating the metabolic microenvironment of tumors, the relationship between viral infection and cancer, and the metabolic changes associated with aging, with the aim of identifying actionable interventions in human aging and disease.

Research topics

• Cell biology
• Biochemistry
• Biology
• Genetics
• Cancer research
• Bioinformatics

Selected publications

• Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

  Nature Cancer · 2022 · 73 citations

  • Biology
  • Cancer research
  • Cell biology

  The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

  DOI

• SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition

  Nature Communications · 2021 · 151 citations

  • Biology
  • Virology
  • Cell biology

  Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.

  DOI

• Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth

  Cell Metabolism · 2021 · 271 citations

  • Biochemistry
  • Biology
  • Cell biology
  DOI

• Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 8 citations

  • Biology
  • Cancer research
  • Cell biology

  Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterogenous and densely fibrotic microenvironment. This limits functional vasculature and diffusion of nutrients through the tumor 1,2 . Accordingly, pancreatic cancer cells develop numerous metabolic adaptations to survive and proliferate in nutrient austere conditions 3-7 . Subtypes of PDA have been characterized by transcriptional and functional differences 8-12 , which have been reported to exist within the same tumor 13-15 . However, it remains unclear if this diversity extends to metabolic programming. Here, using a combination of metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses within neoplastic populations isolated from a single pancreatic tumor. Furthermore, these populations are poised for metabolic crosstalk, and in examining this, we find an unexpected role for asparagine in maintaining cell proliferation following mitochondrial inhibition. Functionally, when challenged by mitochondrial inhibition, asparagine supplementation increases intracellular levels of asparagine and aspartate, a rate limiting biosynthetic precursor 16-18 . Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes pancreatic tumors to mitochondrial targeting with phenformin. Together, these data extend the concept of metabolic diversity to neoplastic populations within individual tumors, while illustrating a new method of intratumoral communication that supports tumor fitness 19,20 . Finally, the combination of asparaginase with mitochondrial inhibition could provide a powerful new strategy for this difficult to treat disease.

  DOI

Frequent coauthors

• Heather R. Christofk

  8 shared

• William B. Tu

  University of California, Los Angeles

  8 shared

• Linda Z. Penn

  University Health Network

  7 shared

• Brian Raught

  Princess Margaret Cancer Centre

  7 shared

• Paul C. Boutros

  University of Toronto

  7 shared

• Dharmendra Dingar

  Université de Montréal

  6 shared

• Sandeep Batra

  Max Super Speciality Hospital

  6 shared

• Manpreet Kalkat

  Van Andel Institute

  5 shared

Similar researchers at University of Southern California

• Norbert Schwarzh-140
• Inderbir S. Gillh-136
• Andreas Molischh-132
• David G. Armstrongh-124
• Antoine Becharah-116