Cellular and Molecular Biology 6 Cancer Biomarkers and Drug Resistance 10 Molecular Chemoprevention and Therapeutics 12 Membrane Biochemistry 16 Structural Biology 20 Nutrition and Metabolism 22 The mission of The Hormel Institute is to conduct research and provide education Cell Death and Cancer Genetics 24 in the biological sciences with applications in medicine and agriculture. In pursuit Cancer Cell Biology and Translational Research 28 of this mission, and as intended by its founders, The Hormel Institute generates Cellular Dynamics 30 Today’s RESEARCH, Tumor Microenvironment and Metastasis 34 Tomorrow’s CURES fundamental knowledge and disseminates it to the scientific community worldwide. Cryo-EM and Molecular Cell Biology 36 It also serves as a center of technical and educational expertise for the benefit of Cancer Epigenetics & Experimental Therapeutics 38 the Austin community, the surrounding region and the State of Minnesota. Laboratory of Stem Cells and Cancer 42 Cell Signaling and Tumorigenesis 44 Molecular Biology and Translational Cancer Research 46 Partners in Growth 50 Expansion 2014 - 16 56 2 The Hormel Institute “Today’s Research, Tomorrow’s Cures.” 3 Message from the Executive Director Dr. Zigang Dong Dear Friends, Throughout 2015-16, milestone progress continued at The Hormel facility and new state of the art technologies. The new labs house the Institute, University of Minnesota. world’s most cutting edge imaging technology - the Cryo-Electron microscope - that captures and develops 2-D and 3-D images at the Our focus on making major contributions to cancer research and subatomic level. This technology is available at very few institutes in the discoveries aimed at preventing cancer and extending lives again made country and will be used for cancer drug development. major leaps forward this year. We had a historic record for grant funding and we became partners with one of the most respected scientific journals The Hormel Institute’s lab sections increased to 15 this year, making our in the world - Nature. center more comprehensive in our study of cancer development and prevention. In this report you will hear from our growing number of Again our Institute grew, thanks to the support of The Hormel Foundation, scientific research leaders, each outstanding in their investigations. and again we doubled the size of The Hormel Institute by adding another 20 state of the art labs and a global communications center named “Ray We are thankful for our growing partnerships and collaborations that bring Live Learning Center” in recognition of the significant contribution of Gary like-minded dedicated scientists and leaders of organizations together to and Pat Ray. This is great progress, especially in light of tripling in size just fight our common enemy, cancer. 8 years ago. Thank you for your faithful support as together we work for answers to The expansion celebration brought leaders and supporters from cancer. We will enjoy a brighter, healthier tomorrow because of today’s throughout the state, country and world to tour the beautiful expanded research and your dedicated friendship. “Most human cancers are preventable, or treatable, if discovered at an early stage.” Dr. Zigang Dong Executive Director 4 The Hormel Institute “Today’s Research, Tomorrow’s Cures.” 5 Cellular and Molecular Biology Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical in coffee that reportedly has anti-cancer activities. The Zigang Dong, M.D., Dr. P.H. underlying molecular mechanisms and targeted proteins involved in Executive Director/Section Leader the suppression of carcinogenesis by caffeic acid, however, are not fully McKnight Presidential Professor in Cancer Prevention Hormel/Knowlton Professor understood. We reported that caffeic acid significantly inhibits colony cancer progression is accompanied by an elevation in epidermal formation of human skin cancer cells and EGF-induced neoplastic growth factor receptor (EGFR) levels. These high levels of EGFR transformation of HaCaT cells dose-dependently. Caffeic acid topically can be attenuated by aspirin intake. The widespread overexpression applied to dorsal mouse skin significantly suppressed tumor incidence of EGFR occurs as a consequence of COX-2 activation in familial and volume in a solar UV-induced skin carcinogenesis mouse model. A adenomatous polyposis (FAP) patients. This study revealed a substantial reduction of phosphorylation in mitogen-activated protein functional association between COX-2 and EGFR expression during kinase signaling was observed in mice treated with caffeic acid either before colon carcinogenesis and provided new strategies for colon cancer or after solar UV exposure. Caffeic acid directly interacted with ERK1/2 and prevention and therapy. inhibited ERK1/2 activities in vitro. Importantly, we resolved the co-crystal structure of ERK2 complexed with caffeic acid. Caffeic acid interacted directly with ERK2 at amino acid residues Q105, D106 and M108. Moreover, 2. Discovery of novel targets and agents for skin cancer A431 cells expressing knockdown of ERK2 lost sensitivity to caffeic acid in a prevention and therapy. skin cancer xenograft mouse model. Taken together, our results suggest that Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, caffeic acid exerts chemopreventive activity against solar UV-induced skin the most common form of cancer in the United States. The carcinogenesis by targeting ERK1 and 2. mitogen-activated protein kinase (MAPK) cascades are activated by SUV irradiation. We found that p38 signaling is critical for skin The Pim-1 kinase regulates cell survival, proliferation, and differentiation, carcinogenesis. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and it is overexpressed frequently in many malignancies, including and stress-activated protein kinase (MSK) proteins constitute leukemia and skin cancer. We used kinase profiling analysis to demonstrate Many proteins are a family of protein kinases that mediate signal transduction overexpressed only in cancer. that 2’-hydroxycinnamicaldehyde (2’-HCA), a compound found in downstream of the MAPK cascades. Phosphorylation of RSK and MSK1 The epidermal growth factor cinnamon, specifically inhibits Pim-1. Co-crystallography studies was upregulated in human squamous cell carcinoma (SCC) and SUV- (green) is highly expressed determined the hydrogen bonding pattern between 2’-HCA and Pim-1. treated mouse skin. Kaempferol – a natural flavonol found in tea, broccoli, in skin tumors and is a major Notably, 2’-HCA binding altered the apo kinase structure in a manner grapes, apples, and other plant sources – is known to have anticancer chemotherapy target in that shielded the ligand from solvent, thereby acting as a gatekeeper loop. activity, but its mechanisms and direct target(s) in cancer chemoprevention breast cancer. Biologically, 2’-HCA inhibited the growth of human erythroleukemia are unclear. Kinase array results revealed that kaempferol inhibited RSK2 or squamous epidermoid carcinoma cells by inducing apoptosis. The Cancer is one of the leading causes of human death worldwide. By focusing and MSK1. Pull-down assay results, ATP competition, and in vitro kinase (Left to right) Front row: Zigang Dong, Ann M. Bode compound also was effective as a chemopreventive agent against EGF- on molecular mechanisms, we continue to discover the key molecular assay data revealed that kaempferol interacts with RSK2 and MSK1 at mediated neoplastic transformation. Lastly, 2’-HCA potently suppressed events in cancer development as well as agents for cancer prevention and the ATP-binding pocket and inhibits their respective kinase activities. Second row: Qiushi Wang, Ge Gao, Tatiana Zykova, Yaping Han, Eunmiri Roh the growth of mouse xenografts representing human leukemia or skin therapy. Mechanistic investigations showed that kaempferol suppresses RSK2 cancer. Overall, our results offered preclinical proof of concept for 2’-HCA Third row: Tara Adams, Ting Wang, GuoGuo Jin, Ruihua Bai, Lichan Chen, Hiroyuki Yamamoto, and MSK1 kinase activities to attenuate SUV-induced phosphorylation Srinivasa Reddy, Seung Ho Shin as a potent anti-cancer principle arising from direct targeting of the Pim-1 1. Discovery of key molecular events in cancer development. of cAMP-responsive element binding protein (CREB) and histone H3 kinase. Fourth row: Wei-Ya Ma, Zhenjiang Zhao, Joohyun Ryu, Kibeom Bae, Souren Paul We found that the prostaglandin thromboxane A2 (TXA2) level is correlated in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced with colorectal cancer progression and this may be used as a marker mouse skin carcinogenesis. Further analysis showed that skin from the Fith row: Christopher Dong, Keke Wang, Tianshun Zhang, Xiaoyu Chang 3. Discovery of novel agents for lung cancer prevention and therapy. for early diagnosis of colon cancer. The TXA2 pathway is constitutively kaempferol-treated mice exhibited a substantial reduction in SUV-induced Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality activated during colorectal tumorigenesis and required for anchorage- phosphorylation of CREB, c-Fos, and histone H3. Overall, our results independent growth of colon cancer cells. Our work lays the foundation for identify kaempferol as a safe and novel chemopreventive agent against introducing a TXA2-targeting strategy for the prevention, early detection SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. 6 The Hormel