Understanding the role of mitochondria in tissue homeostasis and cancer.
The Macleod Lab investigates how control of mitochondrial mass, mitochondrial function and mitochondrial signaling affects cellular responses to stress, homeostatic control of tissue maintenance and influences tumor growth and progression to malignancy. We use cutting edge approaches in cell and molecular biology, systems biology, novel mouse models and human patient samples to ask some of the most important questions about how mitochondria control tissue homeostasis, and how mitochondrial dysfunction contributes to cancer progression and metastasis. For example, we examine how BNIP3-dependent mitophagy is essential for proper metabolic zonation in the liver across the hypoxic gradient making up the liver lobule and how loss of BNIP3 promotes hepatic steatosis and liver cancer. This tumor suppressive role of BNIP3 involves coordinated turnover of lipid droplets with mitochondria at the autolysosome in a process we have termed “mitolipophagy”. In addition, we address how the BNIP3-related protein, BNIP3L (or NIX) which is also a mitochondrial cargo receptor, shares mitophagy functions with BNIP3 but we are increasingly focused on the divergent properties of BNIP3 and NIX in cellular growth control, both in the liver and in the pancreas. Our work indicates that while BNIP3 and NIX share functions in mitophagy in various tissues, they also possess unique growth control properties that explain how BNIP3 functions to suppress tumor growth while NIX acts as a tumor promoter. Ongoing work is addressing these functions in hepatocellular carcinoma, pancreatic ductal adenocarcinoma and in muscle atrophy linked to cancer cachexia. In other areas, we are examining how defects in mitophagy can promote tumor responses to chemotherapy and radiotherapy. Finally, we are examining how mitochondrial stress affects other signaling pathways in the cell.
University of Edinburgh
Scotland
B.Sc. (Hons) - Molecular Biology
The Beatson Institute for Cancer Research, University of Glasgow
Scotland
Ph.D. - Cancer Biology
The Massachusetts Institute of Technology
Cambridge, MA
Post-doctoral fellow - The RB tumor suppressor
DISSECTING TUMOR TRANSCRIPTIONAL HETEROGENEITY FROM SINGLE-CELL RNA-SEQ DATA BY GENERALIZED BINARY COVARIANCE DECOMPOSITION.
DISSECTING TUMOR TRANSCRIPTIONAL HETEROGENEITY FROM SINGLE-CELL RNA-SEQ DATA BY GENERALIZED BINARY COVARIANCE DECOMPOSITION. bioRxiv. 2023 Aug 17.
PMID: 37645713
Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis. Elife. 2023 05 31; 12.
PMID: 37254839
Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner.
Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner. Sci Adv. 2022 Oct 14; 8(41):eabo2510.
PMID: 36223464
ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3.
ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3. Sci Rep. 2021 10 15; 11(1):20526.
PMID: 34654847
Autophagy in major human diseases.
Autophagy in major human diseases. EMBO J. 2021 10 01; 40(19):e108863.
PMID: 34459017
Mitophagy in tumorigenesis and metastasis.
Mitophagy in tumorigenesis and metastasis. Cell Mol Life Sci. 2021 Apr; 78(8):3817-3851.
PMID: 33580835
BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver.
BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver. Autophagy. 2021 11; 17(11):3530-3546.
PMID: 33459136
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy. 2021 Jan; 17(1):1-382.
PMID: 33634751
Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma.
Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma. Cancer Lett. 2020 02 28; 471:49-60.
PMID: 31830557
Autophagy and cancer cell metabolism.
Autophagy and cancer cell metabolism. Int Rev Cell Mol Biol. 2019; 347:145-190.
PMID: 31451213
UCCCC Janet Rowley Discovery Award
University of Chicago
2023
Womens Board Senior Scholar, The Cancer Research Foundation
University of Chicago
2020
Scientist of the Month (November 2018), American Women in Science, Chicago Chapter
University of Chicago
2018
Faculty Marshall, Divisional Academic Ceremony of the Biological Sciences Division
University of Chicago
2016
The Fletcher Scholar Award, The Cancer Research Foundation
University of Chicago
2014 - 2016
Raymond F Zelko Young Investigator, The Cancer Research Foundation
University of Chicago
2002 - 2004
V Foundation Scholar
University of Chicago
2002 - 2004