Kay Macleod, PhD

The deadliest aspect of the majority of human cancers is metastasis, the multi-step process by which cancer cells escape the confines of the primary site (such as breast, pancreas or other organs) and travel in the circulation to distant sites (such as brain, liver or lungs) where they can lodge, invade and grow out as secondary tumors or metastases.

Many factors play into cancer metastasis including how disseminating tumor cells respond to stresses such as nutrient deprivation and altered cellular attachments. These stresses are known to activate a process known as autophagy and research in the Macleod Lab seeks to understand and clarify the role of autophagy in tumor growth and progression to metastasis.

We are particularly interested in understanding how defects in the turnover of mitochondria (the energy factory of the cell) by mitophagy, leads to tumor invasion and metastasis. Our research addresses how mitophagy is induced and how mitophagy contributes to cellular homeostasis. This includes examining how physiological stresses, such as hypoxia and nutrient deprivation remodel the mitochondrial reticulum, how mitochondrial stress is sensed in the cell and how mitophagy is coordinated with other mitochondrial quality control pathways to promote cellular function. These mechanisms are frequently deregulated in cancers and research in the Macleod Lab also examines how defective mitophagy and mitochondrial dysfunction contributes to tumor progression and metastasis. Mitochondria are highly dynamic organelles and while their function in metabolism and control of apoptosis is well known, work in the Macleod Lab also examines how mitochondria modulate cell fate more broadly, including stemness and in metaplasia, and how they modulate cell motility and invasiveness. This is performed using novel mouse models, engineered cell lines and primary human tumor samples with a focus on breast, pancreas and liver cancers.

The Massachusetts Institute of Technology
Cambridge, MA
Post-doctoral fellow - The RB tumor suppressor
1996

Institut Pasteur
France
Post-doctoral fellow - Ets Transcription Factors
1993

The Beatson Institute for Cancer Research, University of Glasgow
Scotland
Ph.D. - Cancer Biology
1990

University of Edinburgh
Scotland
B.Sc. (Hons) - Molecular Biology
1986

Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma.
Schubert AD, Channah Broner E, Agrawal N, London N, Pearson A, Gupta A, Wali N, Seiwert TY, Wheelan S, Lingen M, Macleod K, Allen H, Chatterjee A, Vassiliki S, Gaykalova D, Hoque MO, Sidransky D, Suresh K, Izumchenko E. 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.
Anderson CM, Macleod KF. Autophagy and cancer cell metabolism. Int Rev Cell Mol Biol. 2019; 347:145-190.
PMID: 31451213

Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, Tuveson DA. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer. Cancer Discov. 2019 09; 9(9):1268-1287.
PMID: 31263025

Autophagy, cancer stem cells and drug resistance.
Smith AG, Macleod KF. Autophagy, cancer stem cells and drug resistance. J Pathol. 2019 04; 247(5):708-718.
PMID: 30570140

Dia1-dependent adhesions are required by epithelial tissues to initiate invasion.
Fessenden TB, Beckham Y, Perez-Neut M, Ramirez-San Juan G, Chourasia AH, Macleod KF, Oakes PW, Gardel ML. Dia1-dependent adhesions are required by epithelial tissues to initiate invasion. J Cell Biol. 2018 04 02; 217(4):1485-1502.
PMID: 29437785

Functions of autophagy in the tumor microenvironment and cancer metastasis.
Mowers EE, Sharifi MN, Macleod KF. Functions of autophagy in the tumor microenvironment and cancer metastasis. FEBS J. 2018 05; 285(10):1751-1766.
PMID: 29356327

Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes.
Kathayat RS, Cao Y, Elvira PD, Sandoz PA, Zaballa ME, Springer MZ, Drake LE, Macleod KF, van der Goot FG, Dickinson BC. Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes. Nat Commun. 2018 01 23; 9(1):334.
PMID: 29362370

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors.
Malone CF, Emerson C, Ingraham R, Barbosa W, Guerra S, Yoon H, Liu LL, Michor F, Haigis M, Macleod KF, Maertens O, Cichowski K. 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.
PMID: 28963352

Expanding perspectives on the significance of mitophagy in cancer.
Drake LE, Springer MZ, Poole LP, Kim CJ, Macleod KF. Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol. 2017 12; 47:110-124.
PMID: 28450176

Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth.
Zhou D, Springer MZ, Xu D, Liu D, Hudmon A, Macleod KF, Meroueh SO. Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth. Bioorg Med Chem. 2017 06 15; 25(12):2995-3005.
PMID: 28438385

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