Kay Macleod, Ph.D.

Research Summary

To find out more about research going on in the Macleod Lab, check out the Lab Webpage at www.cancermitochondria.com

Research Summary

Autophagy and Mitochondrial Dysfunction in Cancer.

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. In particular, we are interested in understanding how defects in the turnover of mitochondria (the energy factory of the cell) by autophagy, leads to tumor invasion and metastasis.


Using a variety of approaches from biochemical, molecular, cellular as well as genetic models to in vivo imaging and primary human patient sample analysis, research on the role of autophagy in cancer metastasis in the Macleod Lab is focused on breast cancer, pancreatic cancer and liver cancer. By examining and comparing similarities and differences between how metastasis develops from each of these organ sites, we can appreciate what new molecular targets may be most relevant to understanding and ultimately treating these deadly diseases.


What is Autophagy?

Autophagy is a well-conserved survival mechanism that plays a cellular house keeping function in promoting the regular degradation of protein aggregates, organelles, pathogens and other large intra-cellular structures by autolysosomes -“garbage disposal” – and thus plays a key role in maintaining cellular integrity and promoting efficient cellular function.


Autophagy is also ramped up in response to energy deficits (such as in an ischemic tumor) when it becomes critical for generating ATP and metabolites for survival. Thus, not only is autophagy the “garbage collector” – autophagy also promotes “re-cycling”.


Why is Autophagy important in cancer?
Autophagy plays a complex role in cancer development and treatment that currently appears to vary depending on tissue type, driving oncogene, stage of tumor progression and drug regimen used.

This highlights the need to understand which aspects of autophagy are most critical to its role in cancer if we are to effectively target autophagy for improved cancer therapy.


The diverse functions of autophagy in the cell include promoting amino acid recycling at the lysosome, eliminating unfolded protein and reducing ER stress, turning over mitochondria, recruiting immune cells to tumors and in regulating secretion of cytokines and proteases to break down the basement, and as our recent data shows, promoting focal adhesion dis-assembly to allow tumor cell invasion and metastasis.


Our work has focused on two key consequences of altered autophagy in cancer: (1) dysfunctional mitochondria arising from defects in mitophagy (the process by which mitochondria are selectively degraded at the autophagolysosome), and (2) increased metastasis due to a variety of roles for autophagy in tumor cell invasivion.



Work in the Macleod laboratory is supported by the National Institutes of Health, the Department of Defense Breast Cancer Research Program and generous support from the Y-Me Breast cancer research charity.