Our “Cancer Biology” research section studies the molecular mechanisms and signal transduction pathways involved in vascular permeability, cancer progression/metastasis, cancer drug resistance, and adverse effects of cancer therapy. We employ two talented postdoctoral fellows, Sk. Kayum Alam, Ph.D. and Li Wang, M.D., Ph.D. Over each of the past three summers, Christina Hernandez (2018), Abbygail Coyle (2017), and Erin Dankert (2016) have joined us as summer undergraduate research experience (SURE) interns. They eagerly learned a variety of technical laboratory skills and contributed to aspects of numerous research projects. Our National Institutes of Health funded laboratory was established in the fall of 2015.
Lung cancer is the leading cancer related cause of death in the United States and worldwide. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer and carries a very poor survival rate: less than 15% of patients survive more than five years. Despite administration of front-line chemotherapeutic agents with molecular targeted systemic therapies, the survival rate of NSCLC patients remains dismal due to the large number of individuals diagnosed with advanced stage disease and the primary and secondary resistance to current therapies. Elucidation of new biomarkers and novel precision therapies will help overcome these challenges and make significant strides in improving lung. The primary focus of our research is to develop new therapies to inhibit lung cancer progression and prevent tumor cells from acquiring resistance to current treatments. We accomplish these goals through the use of a variety of models as well as utilization of lung cancer patient samples. Such translational studies will be important for the development of new cancer therapies. Our research aims to improve the dismal survival rate of lung cancer patients and seeks an innovative approach to combatting tumor drug resistance. We seek to identify novel therapeutic targets to help the multitude of Americans suffering from lung cancer.
Vascular endothelial growth factor (VEGF) is required for blood vessel formation and promotes permeability in veins. Tumors produce VEGF because they require their own vasculature to grow, obtain nutrients and oxygen, and eliminate waste products. The permeability induced by VEGF enables cancer cells to escape their primary site, enter the bloodstream, and metastasize to other tissues. Dopamine (DA) and dopamine D2 receptor (D2R) agonists inhibit VEGF-mediated blood vessel development (angiogenesis) and vascular permeability by inhibiting VEGF binding, VEGF receptor phosphorylation and subsequent downstream signaling. Our recent studies demonstrated D2R agonists, including FDA approved cabergoline, inhibit lung cancer growth in in vivo models by reducing angiogenesis and tumor infiltrating immune suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression levels and tumor stage as well as patient smoking history.
- Triggering the dopamine pathway to inhibit lung cancer progression
Currently, we are focused on understanding how a signaling molecule downstream of the dopamine D2 receptor, called DARPP-32 (dopamine and cyclic-AMP-regulated phosphoprotein), can be modulated to inhibit lung cancer growth. Recent studies have demonstrated that elevated expression of DARPP-32 and its truncated splice-variant, t-DARPP, are associated with breast and gastric tumorigenesis. Thus, we hypothesized DARPP-32 and t-DARPP proteins may activate oncogenic signaling that contributes to progression of NSCLC. We demonstrate that overexpression of DARPP-32 and t-DARPP promotes lung tumor growth in human xenograft orthotopic murine models through activation of AKT and ERK signaling. Correspondingly, abrogation of DARPP-32 in human NSCLC cells reduces lung tumor growth in preclinical in vivo models. We identify migration as a cellular mechanism by which DARPP-32 proteins stimulate NSCLC. Our studies suggest a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) promotes NSCLC cell migration through nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-KB2) signaling via the non-canonical p52 pathway. Histopathological analysis of over 60 lung adenocarcinoma patientderived tissues reveals t-DARPP protein overexpression positively correlates with tumor grade, suggesting upregulation of t-DARPP promotes lung adenocarcinoma progression. Evaluation of bioinformatics data corresponding to over 500 lung adenocarcinoma patients confirms elevated t-DARPP expression is associated with worsening tumor grade as well as demonstrates correlation between high t-DARPP levels and poor overall NSCLC patient survival. Taken together, we describe aberrant DARPP-32 isoform expression promotes NSCLC growth and association of DARPP-32 with IKKα stimulates lung cancer cell migration via non-canonical NF-KB2 signaling. Identification of DARPP-32 signaling as a new potential molecular target for NSCLC therapy offers promise to improve the clinical outcome of patients afflicted with lung cancer.
- Development of zebrafish models of vascular permeability and cancer metastasis
VEGF induces vascular permeability in stroke, heart attack, and cancer leading to many pathophysiological consequences. Following cerebral or myocardial infarction, VEGF induces gaps between adjacent endothelial cells in ischemic tissue and the resulting vessel leakiness causes deleterious edema formation and tissue damage. In cancer, VEGF-mediated permeability promotes tumor angiogenesis and metastasis. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of permeability do not exist. We developed a heat-inducible VEGF transgenic zebrafish model through which vascular permeability can be monitored in real-time. Using this approach with protein knockdown, as well as knockout in vivo models, we described a novel role of phospholipase Cβ3 (PLCβ3) as a negative regulator of VEGF-mediated vascular permeability by tightly regulating intracellular calcium release. We have also used this zebrafish model to elucidate the role of RhoC and other molecules in vascular homeostasis. The zebrafish vascular permeability model represents a straightforward method for identifying genetic regulators of VEGF-mediated vascular as promising targets for cancer, heart disease and stroke therapies. We also developed a zebrafish xenograft model of human cancer cell metastasis, which has been used in two separate studies to support our findings from murine cancer models. We are currently using these models to elucidate the molecular regulation of vascular permeability and cancer metastasis.
- Topical treatment of radiotherapy-induced skin damage in breast cancer patients
Over three million women living in the United States have a history of invasive breast cancer. In 2017, an estimated 252,710 new cases of invasive breast cancer will be diagnosed and over 40,000 American women will unfortunately die due to this dismal disease. About half of all breast cancer patients in the United States receive radiation therapy. Radiotherapy uses targeted, high energy X-rays to effectively destroy cancer cells, but healthy skin tissue is also damaged in the process. Radiation-induced skin damage typically manifests as radiation dermatitis, a prevalent side effect affecting approximately 95% of radiotherapy recipients. The effects of radiation dermatitis include pain, itching, poor aesthetic appearance, and chronic reappearance of skin wounds due to pathological changes during the healing process, such as excessive fibrosis. Severe radiation dermatitis occurs in 5-10% of breast cancer patients receiving whole-breast radiotherapy, which leads to delays or stoppage of radiotherapy and increases the risk for cancer recurrence. Common approaches to prevent and reduce radiation-induced dermatitis of the irradiated skin area involve basic moisturizing, cleansing with mild soap, applying topical cortisone creams, and avoiding irritants like scratching or rough clothing. However, reports from a multitude of clinical trials conclude all current radiation dermatitis treatment strategies lack clinical efficacy. Therefore, new treatments that promote recovery from radiation dermatitis are necessary to improve the quality of life and clinical outcome of breast cancer patients by alleviating painful short- and long-term radiation side effects to ensure completion of radiation therapy regimens. The goal of our “Paint the Town Pink” supported work is to define the molecular mechanisms through which radiation causes skin injury and develop a topical treatment for radiation dermatitis. To achieve this aim, we are conducting ongoing studies using an in vivo model of radiotherapy-induced skin injury we developed in collaboration with UMN colleagues.