March 1, 2019:

Investigator Spotlight

Shihuan Kuang, PhD, Purdue University Center for Cancer Research

Educational background

• PhD in Physiology and Cell Biology: University of Alberta

Research interests

My lab mainly aims to understand the molecular regulation of stem cells in the adult skeletal muscle and adipose tissues, and how deregulation of certain signaling pathways underlie diseases including cancer.

Notch signaling is an evolutionarily conserved regulator of stem cell differentiation and tumorigenesis. Activation or inactivation of Notch has been implicated in several types of cancers including leukemia, breast cancer, and osteosarcoma. Using a mouse model, my group has recently made a seminal discovery that Notch activation in mature adipocytes drives their dedifferentiation and formation of liposarcoma (LPS). Human LPS is a deadly and the most common soft tissue cancer whose cellular origin and molecular regulation are unclear. Moreover, currently there is a lack of tractable animal models with which to mimic human LPS. Taking advantage of this novel mouse model, in combination of transcriptomics, lipidomics, cell fate mapping, xenograft models, and funding from the National Cancer Institute, we are now dissecting how Notch activity disrupts the homeostasis between normal adipogenic stem cells and adipocytes, leading to the tumorigenic transformation. In addition, results from animal models will be extended to understanding the pathogenesis and treatment of a subtype of human LPS – the most aggressive dedifferentiated LPS (DDLPS).

A second line of research in the Kuang lab aims to understand the role of PTEN tumor suppressor in stem cells of the skeletal muscle – the satellite cells. In addition to its well-established role in tumor suppression, emerging studies have identified a role of PTEN in several stem cell types. My team uses muscle-specific PTEN knockout mouse models to dissect the in vivo function of this tumor suppressor in homeostatic maintenance of satellite cells and their proper functioning in muscle repair in response to damages or under degenerative disease conditions. As myogenic progenitors are the cell-of-origin for rhabdomyosarcoma (RMS), knowledge about PTEN function in satellite cells may be translated to the understanding of its conserved role in RMS.

Little-known facts about Dr. Kuang

• I am the only member of Purdue University Center for Cancer Research with a primary appointment in the Department of Animal Sciences.
• The four people in my family were born in three different countries.
• I like skiing, jogging, and bicycling.

Thought Leader Perspectives

L. Tiffany Lyle, DVM, PhD, DACVP
Assistant Professor of Veterinary Pathology
Purdue University College of Veterinary Medicine

Brain metastases are increasing in incidence, and there is a continued need for effective treatment to improve patient survival time and quality of life. Metastatic brain cancer occurs most commonly in patients diagnosed with metastatic lung cancer, breast cancer, or melanoma. Quantitatively, brain metastases are diagnosed in 40% of metastatic lung cancer patients, 30% of metastatic breast cancer patients, and 15% of metastatic melanoma patients. In the clinic, brain metastases of breast cancer are often diagnosed in the face of stable systemic disease. By contrast, in lung cancer the diagnosis of brain metastases is made at the primary diagnosis of disease and diagnosis of brain metastases of melanoma are often identified with advanced disease.

Effective and longterm treatment of brain metastases continues to be a clinical challenge. Therapies are improving and include whole brain radiotherapy, stereotactic radiosurgery, surgical resection, immunotherapies, and many other targeted therapies. However, one of the greatest barriers of delivery of effective treatment to the brain is the shift of the blood-brain barrier to the blood-tumor barrier. In the healthy brain, the blood-brain barrier is a network of capillaries that form the tightest and most effective barrier in the body. The blood-brain barrier protects the brain from circulating ions, macromolecules or toxins. This barrier is composed of endothelial cells with distinct tight junctions, a specialized basement membrane, pericytes and astrocyte endfeet. Interaction of endothelial cells with other components of the blood-brain barrier, especially pericytes, is paramount in maintaining an effective barrier (Abbott et al. 2006).

In brain metastases, the blood-brain barrier shifts to the blood-tumor barrier as tumor cells invade the brain tissue. The blood-tumor barrier has been shown to exhibit heterogeneous permeability in brain metastases of breast cancer (Lockman et al. 2010). However, while the blood-tumor barrier is permeable compared to blood-brain barrier, it is not permeable enough to allow drugs to enter the neuroparenchyma. Dr. Tiffany Lyle, assistant professor at Purdue University and principal investigator of the Comparative Blood-Brain Barrier Laboratory, is working to identify the structural changes in the blood-tumor barrier in brain metastases. Her group is identifying molecular tools to manipulate the blood-tumor barrier to improve delivery of drugs to brain metastases and improve the quality of life of patients. To date, Dr. Lyle has identified a correlation of paracellular blood-tumor barrier permeability and altered pericyte subpopulations in brain metastases of HER2+ and triple-negative breast cancer (Lyle et al. 2016). Currently, Dr. Lyle’s group is working with collaborators at Purdue University and the Indiana University Melvin and Bren Simon Cancer Center to characterize the blood-tumor barrier in brain metastases of lung cancer using a mouse model. Using immunofluorescence microscopy and immunohistochemistry, Dr. Lyle’s laboratory has identified striking pathology in their model system that correlates with epithelial-mesenchymal transition, a predictor of metastatic progression (Dieterly et al. in press). Dr. Lyle and her team will continue to identify druggable targets within the blood-tumor barrier to improve drug delivery and survival of patients diagnosed with brain metastases of lung cancer. Scientists and clinicians worldwide are working to address the need to improve drug delivery and targeted therapies to improve survival time and quality of life for patients.

References:

Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53 . doi: 10.1038/nrn1824
Dieterly A, Uzunalli G, Soepriatna A, Goergen CJ, Lyle LT (in press) Epithelial-mesenchymal transition phenotypes in vertebral metastases of lung cancer. Toxicol Pathol

Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR (2010) Heterogeneous Blood‚ Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer. Clin Cancer Res 16:5664–5678. doi: 10.1158/1078-0432.ccr-10-1564

Lyle LT, Lockman PR, Adkins CE, Mohammad AS, Sechrest E, Hua E, Palmieri D, Liewehr DJ, Steinberg SM, Kloc W, Izycka-Swieszewska E, Duchnowska R, Nayyar N, Brastianos PK, Steeg PS, Gril B (2016) Alterations in Pericyte Subpopulations Are Associated with Elevated Blood–Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer. Clin Cancer Res 22:5287

About the Big Ten Cancer Research Consortium: The Big Ten Cancer Research Consortium was created in 2013 to transform the conduct of cancer research through collaborative, hypothesis-driven, highly translational oncology trials that leverage the scientific and clinical expertise of Big Ten universities. The goal of the Big Ten Cancer Research Consortium is to create a unique team-research culture to drive science rapidly from ideas to new approaches to cancer treatment. Within this innovative environment, today’s research leaders collaborate with and mentor the research leaders of tomorrow with the unified goal of improving the lives of all patients with cancer.

About the Big Ten Conference: The Big Ten Conference is an association of world-class universities whose member institutions share a common mission of research, graduate, professional and undergraduate teaching and public service. Founded in 1896, the Big Ten has sustained a comprehensive set of shared practices and policies that enforce the priority of academics in the lives of students competing in intercollegiate athletics and emphasize the values of integrity, fairness and competitiveness. The broad-based programs of the 14 Big Ten institutions will provide over $200 million in direct financial support to almost 9,500 students for more than 11,000 participation opportunities on 350 teams in 42 different sports. The Big Ten sponsors 28 official conference sports, 14 for men and 14 for women, including the addition of men’s ice hockey and men’s and women’s lacrosse since 2013. For more information, visit www.bigten.org.