Dickerson Lab

Research Overview

The overall focus of the laboratory is to identify and understand the mechanisms behind drug resistance and disease progression in cancer. The research program can be divided into three distinct yet complementary areas that interconnect in each of the projects in the laboratory:

  • Identifying drug resistant cell populations
  • Identifying and understanding the drug resistance mechanisms used by these cells
  • Developing strategies or reagents to disrupt these mechanisms

These areas have been developed in parallel with our program in comparative oncology, where we study naturally developing cancers in companion animals (dogs and cats) as models for human disease. Companion animals are susceptible to many of the same types of cancer as humans, and the progression of these cancers is often similar between species. As a result, the answers we obtain in studying drug resistance in companion animals contributes to our ultimate goal of developing strategies for the treatment of cancer in people as well as our pets. Towards this goal, we use a variety of tools including biochemistry, molecular biology, bioinformatics, metabolomics, and imaging methods to study drug resistance and advance treatment approaches in human and canine sarcomas as well as human head and neck cancer and feline oral cancer.

Drug resistance in sarcomas

researchFor over a decade, we have investigated multiple aspects of drug resistance and tumor progression in canine hemangiosarcoma, which is a common, highly aggressive cancer in dogs. In collaboration with Dr. Jaime Modiano, we recently identified a novel subclassification of hemangiosarcomas that has provided a foundation to further our understanding of the cellular characteristics of these tumor cells. Our findings have also allowed us to establish the utility of this disease as a spontaneous model to understand the pathogenesis of a similar tumor in humans known as angiosarcomas. Human angiosarcomas exhibit pathological features, morphological organization, and clinical behavior virtually indistinct from canine hemangiosarcomas.

We recently identified several drug resistance mechanisms in hemangiosarcomas, including the ability of a specific subpopulation of tumor cells to sequester the chemotherapy drug doxorubicin within their lysosomes. Drug sequestration within lysosomes prevents the drug from reaching its intracellular targets, allowing the cancer cells to circumvent the drug’s effects and survive. We also found that this same population and drug resistance mechanism operating in human angiosarcomas, highlighting lysosomal drug sequestration as a common feature of resistance and underscoring how studies in dogs may be especially relevant to understanding the human disease. Much of our effort is geared toward understand how these drug resistant populations are maintained and designing strategies to overcome or circumvent the identified drug resistant mechanisms.

Beta adrenergic signaling in sarcomas

researchIn collaboration with Dr. Brad Bryan, we are investigating the role of beta adrenergic receptors (β-ARs) in the pathogenesis of angiosarcoma and hemangiosarcoma. Basic and preclinical studies have demonstrated that these tumors are sensitive to beta adrenergic receptor antagonists, and these results have recently translated into the clinical setting. Other studies by the Dickerson and Bryan groups suggest that beta adrenergic signaling contributes to drug resistance in these tumors through a variety of mechanisms, including alterations in cellular metabolism. We are currently using beta blockade as a tool to decipher the metabolic needs of these sarcomas and determine how these metabolic pathways contribute to drug resistance.

Drug resistant cell populations in head and neck cancer

researchHead and neck squamous cell carcinoma (HNSCC; head and neck cancer) is associated with high morbidity and mortality, due to both the anatomy of the disease site and the inevitable development of drug resistance. One cause of treatment failure is the presence of cells that possess properties similar to those of cancer stem cells (CSC), or CSC-like cells. The mechanisms through which CSC-like populations are maintained remain an important gap in our knowledge of HNSCC pathogenesis.

 

We recently identified a mechanism wherein inhibition of bone morphogenetic protein (BMP) signaling potentiates the long-term stability of a CD44high CSC-like population. We are working closely with Dr. Raj Gopalakrishnan, whose area of expertise is in BMP signaling, to understand this process and take advantage of the recent identification of new drug targets to selectively attack CSC-like cells. CD44 is also a major ligand for hyaluronan (HA), a main component of the extracellular matrix, and interaction between HA and CD44 may function to maintain the CD44high cell population in HNSCC by modulating BMP signaling. Studies in this area are being done in collaboration with Drs. Raj Gopalakrishnan, Jim McCarthy, and Kaylee Schwertfeger.

The contribution of metabolism to drug resistance in oral cancer

researchThe lack of effective treatments for feline OSCC has led our efforts to pursue new strategies to treat this disease. Strong similarities between feline and human oral cancers allow feline OSCC to serve as a spontaneous, large animal model for the human disease, providing translational potential. We are using inhibitors designed by Dr. Les Drewes and his colleagues that inhibit monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4). MCT1 and MCT4 regulate the flux of glycolytic metabolites between tumor cells and the surrounding stroma, allowing for the efficient use of nutrients by tumor cells. We are also investigating the role of fatty acid metabolism in feline and human oral/head and neck tumors, and the potential to use these pathways as a therapeutic target.

© 2021-11-30, All Rights Reserved.
Dickerson Laboratory | University of Minnesota Feedback/Questions

Design by Big Rose Web Design

Location
Masonic Cancer Center
Mayo Mail Code 806
420 Delaware Street SE
Minneapolis, MN 55455

Contact Info
Phone: (612) 625-0365
Email: edickers@umn.edu