Kay Macleod

Research Summary
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.
Cancer, Mitochondria, Autophagy, Tumor metabolism, Stress Responses, Cell Migration & Invasion, Metastasis
  • 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
Biosciences Graduate Program Association
Awards & Honors
  • 2002 - 2004 Raymond F Zelko Young Investigator, The Cancer Research Foundation University of Chicago
  • 2002 - 2004 V Foundation Scholar University of Chicago
  • 2014 - 2016 The Fletcher Scholar Award, The Cancer Research Foundation University of Chicago
  • 2016 - Faculty Marshall, Divisional Academic Ceremony of the Biological Sciences Division University of Chicago
  • 2018 - Scientist of the Month (November 2018), American Women in Science, Chicago Chapter University of Chicago
  • 2020 - Womens Board Senior Scholar, The Cancer Research Foundation University of Chicago
  • 2023 - UCCCC Janet Rowley Discovery Award University of Chicago
  1. Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner. Sci Adv. 2022 Oct 14; 8(41):eabo2510. View in: PubMed

  2. ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3. Sci Rep. 2021 10 15; 11(1):20526. View in: PubMed

  3. Autophagy in major human diseases. EMBO J. 2021 10 01; 40(19):e108863. View in: PubMed

  4. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy. 2021 Jan; 17(1):1-382. View in: PubMed

  5. Mitophagy in tumorigenesis and metastasis. Cell Mol Life Sci. 2021 Apr; 78(8):3817-3851. View in: PubMed

  6. BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver. Autophagy. 2021 11; 17(11):3530-3546. View in: PubMed

  7. 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. View in: PubMed

  8. Autophagy and cancer cell metabolism. Int Rev Cell Mol Biol. 2019; 347:145-190. View in: PubMed

  9. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer. Cancer Discov. 2019 09; 9(9):1268-1287. View in: PubMed

  10. Autophagy, cancer stem cells and drug resistance. J Pathol. 2019 04; 247(5):708-718. View in: PubMed

  11. Dia1-dependent adhesions are required by epithelial tissues to initiate invasion. J Cell Biol. 2018 04 02; 217(4):1485-1502. View in: PubMed

  12. Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes. Nat Commun. 2018 01 23; 9(1):334. View in: PubMed

  13. Functions of autophagy in the tumor microenvironment and cancer metastasis. FEBS J. 2018 05; 285(10):1751-1766. View in: PubMed

  14. mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors. Cancer Discov. 2017 12; 7(12):1450-1463. View in: PubMed

  15. Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis. Autophagy. 2017; 13(12):2086-2103. View in: PubMed

  16. Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol. 2017 12; 47:110-124. View in: PubMed

  17. Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth. Bioorg Med Chem. 2017 06 15; 25(12):2995-3005. View in: PubMed

  18. Autophagic degradation of focal adhesions underlies metastatic cancer dissemination. Mol Cell Oncol. 2017; 4(2):e1198299. View in: PubMed

  19. Autophagy in cancer metastasis. Oncogene. 2017 03 23; 36(12):1619-1630. View in: PubMed

  20. In Brief: Mitophagy: mechanisms and role in human disease. J Pathol. 2016 11; 240(3):253-255. View in: PubMed

  21. Novel insights into how autophagy regulates tumor cell motility. Autophagy. 2016 09; 12(9):1679-80. View in: PubMed

  22. Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastatic Tumor Cells through the Direct Interaction of Paxillin with LC3. Cell Rep. 2016 05 24; 15(8):1660-72. View in: PubMed

  23. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12(1):1-222. View in: PubMed

  24. Tumor suppressor functions of BNIP3 and mitophagy. Autophagy. 2015; 11(10):1937-8. View in: PubMed

  25. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep. 2015 Sep; 16(9):1145-63. View in: PubMed

  26. Correlation of In Vivo and Ex Vivo ADC and T2 of In Situ and Invasive Murine Mammary Cancers. PLoS One. 2015; 10(7):e0129212. View in: PubMed

  27. Mitophagy and cancer. Cancer Metab. 2015; 3:4. View in: PubMed

  28. Measuring autophagy in stressed cells. Methods Mol Biol. 2015; 1292:129-50. View in: PubMed

  29. Mammary cancer initiation and progression studied with magnetic resonance imaging. Breast Cancer Res. 2014 Dec 16; 16(6):495. View in: PubMed

  30. High resolution 3D MRI of mouse mammary glands with intra-ductal injection of contrast media. Magn Reson Imaging. 2015 Jan; 33(1):161-5. View in: PubMed

  31. p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors. PLoS One. 2014; 9(3):e90171. View in: PubMed

  32. Mitochondrial dysfunction in cancer. Front Oncol. 2013 Dec 02; 3:292. View in: PubMed

  33. Tumour suppressor gene function in carcinoma-associated fibroblasts: from tumour cells via EMT and back again? J Pathol. 2014 Feb; 232(3):283-8. View in: PubMed

  34. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr; 8(4):445-544. View in: PubMed

  35. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol. 2012 Jul; 32(13):2570-84. View in: PubMed

  36. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell. 2011 Sep 13; 20(3):400-13. View in: PubMed

  37. MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression. Int J Cancer. 2012 Feb 01; 130(3):509-20. View in: PubMed

  38. The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer? J Clin Invest. 2010 Dec; 120(12):4179-82. View in: PubMed

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  41. Elevated poly-(ADP-ribose)-polymerase activity sensitizes retinoblastoma-deficient cells to DNA damage-induced necrosis. Mol Cancer Res. 2009 Jul; 7(7):1099-109. View in: PubMed

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  44. c-Jun NH2-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4-mediated inhibition of SKOV3ip.1 ovarian cancer metastasis involves growth arrest and p21 up-regulation. Cancer Res. 2008 Apr 01; 68(7):2166-75. View in: PubMed

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  46. Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts. Mol Cell Biol. 2007 Dec; 27(24):8713-28. View in: PubMed

  47. Effects of hypoxia on heterotypic macrophage interactions. Cell Cycle. 2007 Nov 01; 6(21):2620-4. View in: PubMed

  48. Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy. 2007 Nov-Dec; 3(6):616-9. View in: PubMed

  49. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol. 2007 Sep; 27(17):6229-42. View in: PubMed

  50. Hypoxic stress underlies defects in erythroblast islands in the Rb-null mouse. Blood. 2007 Sep 15; 110(6):2173-81. View in: PubMed

  51. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci U S A. 2007 Apr 17; 104(16):6794-9. View in: PubMed

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  54. The Rb tumor suppressor is required for stress erythropoiesis. EMBO J. 2004 Oct 27; 23(21):4319-29. View in: PubMed

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