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Read the Demehri Lab 2017-2018 Annual Report
Shadmehr (Shawn) Demehri, M.D., Ph.D.Assistant Professor of DermatologyMassachusetts General Hospital Cancer CenterHarvard Medical School
The focus of the Demehri laboratory is to determine the role of the immune system in regulating the early stages of cancer development in order to harness its anti-tumor potential for cancer therapy. To date, several cancer immunotherapies have been developed with proven efficacy against late-stage cancers; however, the role of the immune system in preventing the early development of cancer remains uncertain. The research in our laboratory is focused on identifying the immune mechanisms that drive an immune activation sufficient to prevent cancer formation from pre-cancerous lesions. This approach raises a great opportunity to discover novel immune pathways that can be leveraged in cancer therapy and prevention.
Immune Regulation of Cancer Development
Shadmehr (Shawn) Demehri, M.D., Ph.D.Assistant ProfessorMassachusetts General HospitalHarvard Medical School
B.S.: Biology, Washington State UniversityM.D.: Washington University in St. LouisPh.D.: Cell and Molecular Biology, Washington University in St. LouisResidency: Dermatology, Barnes Jewish Hospital/ Washington UniversityPostdoctoral Fellowship: Immunology, Washington University in St. Louis
Howard Hughes Medical Institute Medical Research Fellow
B.S.: (Distinction), Molecular, Cellular, and Developmental Biology Intensive Major, Yale College M.D.: Harvard Medical School (in progress)
Amir received his B.S. in Molecular, Cellular, and Developmental Biology from Yale College. At Yale, he developed a protocol for the synthesis of manganese-based MRI contrast agents for cell tracking and epitope identification. He also studied the role of the tumor suppressor gene, RASSF1A, and oncogene, CTNNB1, in the progression of adrenocortical carcinoma. At the National Cancer Institute, he helped identify a key signaling molecule downstream of the TWEAK – Fn14 pathway that plays a critical role in the promotion of prostate cancer bone metastasis. At Harvard Medical School, he used drug screens to distinguish the PI3K/AKT and Notch signaling pathways as vulnerable targets in breast circulating tumor cell lines. He also used CRISPR - Cas9 genome editing to demonstrate the role of the mTORC1 pathway’s amino acid-sensing arm in the progression of acute leukemia. In the Demehri Laboratory, he is investigating the mechanism of cancer promotion in the context of chronic inflammation.
B.S.: Biochemistry, Molecular and Cellular Biology University of New Hampshire (UNH) M.D.: candidate 2020 University of Massachusetts Medical School (UMMS)
Mary is currently pursuing her medical degree at the University of Massachusetts Medical School. She previously studied the role of master transcription factors on the epigenetic landscape of varying pediatric cancers at MGH. Mary hopes to leverage her cancer and biochemistry background to better understand the role of the Human Papilloma Virus and the oncogenesis of non-melanoma skin cancers.
B.Sc.: Biotechnology, University of Turin, Italy M.Sc.: Medical biotechnologies, Regenerative Medicine, University of Florence, Italy Ph.D.: Immunology, University of Oslo, Norway
Margherita received her PhD in immunology studying how NK cells pre-activated in vitro with IL-12, IL-15, and IL-18 can be used as therapeutic tool to treat T-cell acute lymphoblastic leukemia in animal models. In a parallel project, she studied the contribution of the different Th population to the development of experimental acute GvHD in animal models. She plans to focus her studies into the role of CD4+ T cells and NK cells in antitumor immunity.
B.S.: Biomedical Science, The University of Adelaide, Australia B.S. (Honours): Immunology, The University of Adelaide, Australia Ph.D.: Immunology, The University of Adelaide, Australia
Mark obtained his Ph.D. in chemokine biology focusing on the atypical decoy chemokine receptor, ACKR4/CCX-CKR. ACKR4 expression in the skin was found to be critical for robust trafficking of antigen-loaded dendritic cells to the lymphatic endothelium while thymic ACKR4 expression was required for normal thymocyte development. The absence of ACKR4 led to development of a Sjögren’s syndrome-like disease. Mark then worked as a postdoctoral fellow in the Bone Marrow Transplantation laboratory at QIMR in Brisbane, Australia to understand how graft-versus-host disease impacts NK cell reconstitution post-transplant and the contribution of mucosal innate lymphoid cells to providing protection from this disease. His current work in the Demehri laboratory is focused on NK cell activation and tumor immunity.
B.A.: Biochemistry, Smith College M.S.: Human Physiology, Boston University
Katie comes to our lab having recently completed a Master of Science degree in Human Physiology from Boston University. Though her background is in clinical research and patient care, she hopes to gain laboratory experience and advance her skills to further contribute to laboratory studies. She looks to apply her interest in genetics to the field of cancer biology, immunology and gain knowledge of the innate immune system’s role in cancer.
B.S.: Pharmacy, Kanazawa University Ph.D.: Pharmacy, Kanazawa University
Tatsuya received his Ph.D. degree in Pharmacy in 2008 studying the role of antioxidants compounds from E. globulus and Sasa kurilensis as anti-inflammatory as well as anti-melanogenesis agents. During his postdoctoral training, Tatsuya studied the role of inflammasome and autophagy in skin inflammatory responses. He is interested in understanding the changes in skin immunity in response to cellular damage like UV radiation.
Isabella is currently pursuing her BA in Molecular and Cellular Biology at Harvard University. She has previously researched oncolytic vaccinia virus and cytotoxicity assays at the University of Pittsburgh and IovanceBiotherapeutics. Isabella is assisting the Demehri lab in the effort to study the role of TSLP in lung and pancreatic cancer immunity.
B.S. & M.D.: Clinical Medicine of Eight-year Program, Sun Yat-sen University, China
Kaiwen obtained his M.D. in 2014 and then worked as a urologist as well as researcher in Sun Yat-sen Memorial Hospital, Sun Yat-sen University. He has been involved in research to elucidate the mechanism of castration-resistant prostate cancer and bladder cancer development in Sun Yat-sen Memorial Hospital. Kaiwen is studying the underlying mechanism mediating immunity against tumors with high mutational load.
Bachelor of Medicine: Clinical Medicine, Dalian Medical University, China Master of Medicine: Otolaryngology Head and Neck Surgery, Peking University Health Science Center, China M.D: Otolaryngology Head and Neck Surgery, Peking University Health Science Center, China
Tiancheng specialize in head and neck carcinoma. At Peking University, he has directed research projects on 1) studying Cetuximab hypersensitivity reaction and the effect of this hypersensitivity reaction on head, neck and colorectal cancer prognosis (basic research); and 2) applied research on a new endoscopic assisted hidden incision in the parotid gland tumor Surgery (clinical research). Currently, Tiancheng is supported by the China Scholarship Council to expand his research into the field of cancer immunology. In the Demehri laboratory, he is mainly investigating the role of the immune response to Human Papilloma Virus in cancer development.
Elena is a current undergraduate at Harvard University completing a B.A. in Chemical and Physical Biology. Her interests involve cancer biology and immunology. Her previous research involvement was in the University of Miami Miller School of Medicine, where she participated in projects with the goal to potentiate the immune system in order to battle breast cancer. Elena participates in studies on the tumor-promoting role of the immune system in early stage cancer.
B.A.: Biochemistry and Molecular Biology (Honors, Summa Cum Laude)
Jon is a recent graduate of the Biochemistry and Molecular Biology program at Boston University. He started his research career at Lankenau Institute for Medical Research studying the effects of indoleamine 2,3-dioxygenase 2 (IDO2) in the development and progression of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. At Boston University, he characterized a novel multiple cysteine cluster Toll-Like Receptor and discovered the first pathogen in a coral immunity model organism. Jon hopes to take the insight and technical skills he develops in Demehri lab onto his future career as an oncologist. In addition to treating patients, he plans to study methods of immune modulation in solid tumors to develop novel therapeutics for cancer treatment. Jon has joined the research efforts into role of chronic inflammation in cancer promotion.
Research Technician (Lab Manager)
B.S.: Biomedical Sciences, Boston UniversityResearch Animal Specialist: Boston University
Ken joined our lab as a BU student with strong interest in the field of cancer biology and immunology. In the upcoming months, he will be assisting the Demehri lab in the effort to identify the factors in a Th2 immune environment that are critical for suppression of early stages of cancer development. He hopes to pursue a master in bioinformatics, so that he can further advance his skill set and contribute to the research in the lab.
B.Sc.: Computer Science Engineering and Biomedical Science, Pusan National University, Pusan, Korea M.S. & Ph.D.: Biological Science, Seoul National University, Seoul, Korea
Jongho received his Ph.D. in biological science in 2016 studying protein modifications, such as ubiquitination and SUMOylation. He demonstrated a novel post-translational modification of tumor suppressor DBC1 and p53 induced by DNA damage, which can lead to upregulation of their suppressor activity. During his work in industry, Jongho has investigated the mechanism of rare genetic diseases, such as hemophilia, for the development of new therapeutic antibodies. His current work in the Demehri laboratory is focused on molecular signaling pathway within keratinocyte that can govern skin cancer immunity.
B.A.: English/Pre-Med, Columbia UniversityM.S.: Materials Science and Engineering (Biomaterials), Boston University (Degree in process)
Erik joined our lab as a student pursuing his Master of Science degree in Materials Science and Engineering (Biomaterials) from Boston University. He has been involved in research at the Physiology and Biophysics Department of the University at Buffalo and the Ames National lab. Erik has joined our research effort into understanding the role of NK cells in tumor immunity and assists in other laboratory studies on cancer immunology.
Jackson is currently pursuing his BA in Chemistry at Harvard College. He has previously researched the origin of ovarian cancer at the Yale School of Medicine. Jackson is assisting the Demehri lab in the effort to understand the role of NK cell immunity in regulating carcinogenesis in epithelial organs.
Alumni: Trevor Cunningham Roy Feng, M.D. Aeden Ghebreselassie, MSN, NP-CSophia LeeSara Moradi Tuchayi, M.D., M.P.H. Anniek ZaalbergAnna Zemel, Ph.D.
The field of cancer immunology has made substantial advances in recent years by deciphering the role of the tumor infiltrating CD8+ cytotoxic T lymphocytes (CTLs) in attacking cancer cells, which have led to promising new cancer immunotherapeutics. The current immunotherapeutic approaches, however, are largely designed to boost the anti-tumor immune response that has already formed against late-stage metastatic cancers. Therefore, the current cancer immunotherapies like immune checkpoint blockade, which rely on a pre-existing CTL infiltrate in the tumor for their effects, are proven ineffective to treat cancers that frequently lack a significant anti-tumor immune infiltrate, especially during the early in-situ phases of their development. In order to expand the potential of cancer immunotherapy, our laboratory studies the pathways that lead to immune system activation against early phases of cancer development. Devising a mechanism to activate the immune system against early-stage cancers has clear immunopreventive implications by directly blocking the cancer promotion and immunotherapeutic benefits by potentiating the immunity against late disease.
CD4+ T cell-mediated immunity against breast cancer development
To pursue this goal, our laboratory is currently focused on three areas of research:
(1) Mechanisms of T cell activation against cancer. Our laboratory has studied the mechanism of thymic stromal lymphopoietin (TSLP) in evoking tumor resistance. TSLP is an epithelial-derived cytokine that plays a central role in stimulating CD4+ T helper 2 (Th2)-mediated allergic diseases like atopic dermatitis and asthma. We have shown that high TSLP levels establish a dominant anti-tumorigenic immune environment preventing cancer promotion. Currently, our team investigates the detailed mechanism of TSLP anti-tumor function against solid cancers and examines its application for the treatment of pre-cancerous skin lesions in patients.
(2) Mechanisms of natural killer (NK) cell recruitment and activation against cancer. NK cells are known for their potent anti-tumor properties. However, their role in controlling the cancer development in vivo remains unclear. Our laboratory is utilizing a virally encoded ligand for NK cells to determine the combination of signals necessary to activate NK cells against early stages of carcinogenesis and to identify the mechanism of anti-tumor immunity mounted by the activated NK cells in order to block cancer promotion and progression.
(3) Mechanisms of tumor promotion by the immune system. Although immune cells can mount anti-tumor immunity against cancer, they are also implicated in promoting cancer development under certain conditions. Chronic inflammation is one of the conditions that can predispose patients to cancer; however, the mechanism of such immune-mediated tumor promotion is unclear. To determine this mechanism, our laboratory studies skin carcinogenesis as an ideal cancer model in which the spatial and temporal relationship between inflammation and cancer development can be determined with exceptional precision. We are currently investigating the immune mechanisms that promote skin cancer development in the context of chronic allergic contact dermatitis and cutaneous lupus.
Postdoctoral Research Fellow position is available for a highly motivated individual with expertise in immunology, cancer biology and genomics. Expertise in biochemical, immunological and mice experimentations are required for this position.
Interested candidates should send their information including CV and the name of 2-3 references to Dr. Shawn Demehri: firstname.lastname@example.org
For the full list of publications from the Demehri lab, please visit PubMed here.
Cunningham, T.J., Tabacchi, M., Eliane, J.P., Tuchayi, S.M., Manivasagam, S., Mirzaalian, H., Turkoz, A., Kopan, R., Schaffer, A., Saavedra, A.P., Wallendorf, M., Cornelius, L.A., and Demehri, S. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 2017; 127(1): 106-116.
Demehri, S., Cunningham, T.J., Manivasagam, S., Ngo, K.H., Moradi Tuchayi, S., Reddy, R., Meyers, M.A., DeNardo, D.G., and Yokoyama, W.M. Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis. J Clin Invest 2016; 126(4): 1458-70.
Demehri, S., Turkoz, A., Manivasagam, S., Yockey, L.J., Turkoz, M., and Kopan, R. Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. Cancer Cell 2012; 22(4): 494-505.
Demehri, S., Turkoz, A., and Kopan, R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 2009; 16(1): 55-66.
Demehri, S., Morimoto, M., Holtzman, M.J., and Kopan, R. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 2009; 7(5): e1000067.
Demehri, S., Liu, Z., Lee, J., Lin, M.H., Crosby, S.D., Roberts, C.J., Grigsby, P.W., Miner, J.H., Farr, A.G., and Kopan, R. Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol 2008; 6(5): e123.
Our laboratory is located at the MGH-Charlestown Navy Yard, a historic neighborhood in Boston!
Demehri LabCutaneous Biology Research CenterBuilding 149 13th Street, 3rd floorCharlestown MA 02129Phone: 617-724-8128Email: email@example.com
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