Faculty Bio:
Dr. Mulligan completed her PhD in Biology at Queen’s University and went on to further training focusing on molecular genetics of rare cancer syndromes. Her research on the molecular mechanisms of inherited thyroid cancers led to the discovery of the role of the RET oncogene in endocrine tumours and its contributions to a number of other cancers. Dr. Mulligan holds the Bracken Chair in Genetics and Molecular Medicine and is a Professor of Pathology and Molecular Medicine, and a member of the Division of Cancer Biology and Genetics at the Sinclair Cancer Research Institute at Queen's University. Her primary research interests are in understanding the molecular, cellular, and clinical roles of the RET receptor tyrosine kinase in normal and cancer cells.
Research Interests:
MOLECULAR MECHANISMS OF CANCER PROGRESSION AND METASTASIS
TUMOUR-NERVE CROSSTALK IN CANCER SPREAD
REGULATION OF THE RET RECEPTOR TYROSINE KINASE
EXPLORING POTENTIAL THERAPEUTIC TARGETS IN HUMAN CANCER
Receptor tyrosine kinases link extracellular signals with intracellular pathways that cause cells to move, grow, proliferate, or differentiate. These roles are essential to normal development but can be hijacked in human cancers. The primary interest of our group is the relationship between these normal and neoplastic processes. We focus on the functions and regulation of the RET receptor tyrosine kinase and its roles in normal development and in the growth and spread of several challenging to manage human cancers. Mutations that inappropriately activate RET are found in many cancers including thyroid, adrenal, and lung tumours, but increases in normal RET expression are also associated with human disease including breast, colon, and pancreatic cancers. We focus on dissecting the mechanisms regulating normal RET function and how changes in regulation can lead to cancer growth and spread. Understanding these mechanisms will allow us to identify novel targets for future therapeutic interventions in RET-mediated cancers.
RECENT RESEARCH FROM OUR LAB:
Enhanced Cell Membrane RET Expression Through Disrupted Membrane Dynamics Promotes Cancer
Internalization of proteins from the cell membrane and transition through intercellular compartments are important regulators of signaling in normal cells that can frequently be disrupted in cancer. In this study we showed that loss of a membrane protein called TMEM127 causes normal RET protein to accumulate on the cell surface in adrenal cancers, where increased receptor density promotes its activity and downstream signaling, driving cell proliferation. We showed that TMEM127 is an important determinant of membrane organization and recruitment and stabilization of membrane protein complexes and that loss of TMEM127 reduces internalization and degradation of cell surface RET. Our data provide a novel paradigm for oncogenesis in adrenal cancers where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.
Cellular Mechanisms of RET Receptor Dysfunction in Multiple Endocrine Neoplasia 2.
The RET oncogene is mutated in the familial cancer syndrome Multiple Endocrine Neoplasia type 2, which is characterized by thyroid and adrenal cancers. These mutations cause the RET receptor to be active constitutively in the absence of stimulation by ligands. But is that all there is to it? In this review article that highlights some of our current research areas, we explore the intrinsic and extrinsic effects of these mutations on the RET protein and its functions, and discusses the relative impacts of different mutations on RET and how these affect disease severity.
RET-Targeting Therapies in Clinical Application
N Engl J Med 2023;389:1913-1916
Cell 2023;186:1517
The RET proto-oncogene encodes a receptor tyrosine kinase that can act as a driver in cancers of the lung, thyroid, and adrenal gland. Selective RET inhibitors have been recently approved for treatment of RET-mutation positive tumours and have significant impacts on patient progression free survival. Check out these recent overviews on selective RET inhibition for more information.
Publications
Mulligan Lab on Bluesky: @mulliganlab.bsky.social