Program Activities and Selected Scientific Reports
Led by Patricia Ernst, PhD and Konstantin Dragnev, MD, Cancer Mechanisms is one of six foundational Research Programs at Norris Cotton Cancer Center. Membership of Cancer Mechanisms is comprised of 22 members from 9 departments at Geisel School of Medicine including Genetics, Biochemistry, Medicine, Pediatrics, Community and Family Medicine, Pathology, Pharmacology & Toxicology, Microbiology & Immunology, and Biological Sciences. Cancer Mechanisms meets monthly for program meetings to discuss common interests and share research updates and findings.
Cancer Mechanisms plans and sponsors a number of academic activities each year including an invited talk by the Leighton Core in 2012, a focus group on CRISPR technology by member Michael Cole in 2014, and the annual Lung Cancer Retreat held in May. Symposia led by members bring investigators together from many parts of Dartmouth and our region. Recently they included the Dartmouth Leukemia Mini-Symposium organized by Patricia Ernst, the Life Sciences Symposium planned by Duane Compton, PhD, and the New England Regional Chromosome Pairing meeting coordinated by Giovani Bosco, PhD.
Science in the Dartmouth academic community is enriched by members of Cancer Mechanisms who participate in Pathology Seminars, Bench-to-Bedside Seminars, and Cancer Center Grand Rounds. They gather with others for the Immuno Training Program meetings, the Developmental Research Club, and with UMass for leukemia/lymphoma meetings.
Onsite at Norris Cotton Cancer Center located at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, members of Cancer Mechanisms are embedded in several disease-site specific tumor boards. Konstantin Dragnev and Vincent Memoli, MD are members of the Comprehensive Thoracic Oncology tumor board (known as CTOP), and James DiRenzo, PhD is a member of the Breast Tumor Board.
Dartmouth journal clubs provide opportunities to discuss the advancement of science with great specificity. For example, Patricia Ernst caucuses with interested scientists at the Micro/Gene 271 Chromatin Structure/Function journal club. Richard Mako Saito, PhD runs the Gene 267 Developmental Genetic journal club and both Mark Israel, MD and Michael Cole, PhD lead the Bioc261 Cancer Biology journal club. Harry Higgs, PhD directs the Bioc259 Actin Cytoskeleton group. Amy Gladfelter, PhD and Jamie Mosely, PhD organize the Biol263 Cell Biology journal club.
Dartmouth-sponsored symposia are frequent events and Cancer Mechanisms members are active participants and speakers. Scott Gerber, PhD was involved in the 2011 Genomic Stability Symposium and Harry Higgs, PhD shared new findings at the 2013 Life Sciences Symposium.
Together, members of Cancer Mechanisms help each other to achieve professional goals through thoughtful mentoring, establishing new funding, recruiting new faculty to build programmatic strength, and teaching in graduate programs. The Yolanda Sanchez, PhD, ___ Socolovsky, PhD, and Patricia Ernst pilot grant proposal is a recent example of program members joining forces to seek funding. Recruitment of new investigators who will contribute to the Program is a top priority and recent successes include Giovani Bosco's recruitment into Genetics led by a team of Patricia Ernst, Mako Saito, Michael Cole, and Ashi Ahmed, PhD. Another team of Michael Whitfield, Patricia Ernst, MakoSaito, Michael Cole, and Ashi Ahmed recruited both Casey Greene, PhD and Chao Cheng, PhD into the rapidly growing department of Bioinformatics.
Throughout the Cancer Center, mentoring is a top priority and essential part of our design to help investigators be productive and achieve their goals. In Cancer Mechanisms, Patricia Ernst mentors Chao Cheng and Manabu Kurokawa, PhD by reviewing their grants prior to submission and helping them to refine their overall strategies. Similarly, Konstantin Dragnev mentors fellow thoracic surgeon Cherie Erkmen, MD and Samira Shojaee, MD who shares a focus on pulmonary medicine.
Members of Cancer Mechanisms are leaders on the national scene serving on study sections such as Patricia Ernst's membership in MCH 2012-2018, Konstantin Dragnev and Michael Whitfield's ad hoc involvement, Jim DiRenzo's membership on the Komen study section, and Scott Gerber's work in the ACS study section. They serve on national advisory boards including Patricia Ernst's membership in the International Society for Hematology and Stem Cells, Giovani Bosco's membership in the Genetic Society of America Drosophila Board, and Konstantin Dragnev's membership on the ALLIANCE board of directors.
2013 Selected Scientific Progress & Achievements
The role of c-Myc in cancer has been a focus of Michael Cole’s work since the 1980’s, when he identified this gene as activated by translocation to immunoglobulin regulatory elements in plasmacytoma. Recently, his work in collaboration with Jason Moore (CEC) has turned to exploit genome-wide association studies (GWAS) data to identify sequence nucleotide polymorphisms in breast, prostate, and colorectal cancer that may influence a patient’s risk.
Dr. Radu Stan has a long-standing interest in endothelial cell biology that has led him to study the role of a cellsurface receptor, PV1, in a capillary structure called fenestrae. His program interactions recently led to SBIR proposals to commercialize blocking antibodies for applications in cancer.
Work integrating angiogenesis/tumor microenvironment, melanoma (both laboratory-based models and clinical), immunology, and gene expression expertise has elucidated mechanisms of matrix metalloproteinase (MMPs) regulation and its role in tumor heterogeneity and progression (Croteua 2013).
New computational methods (Dr. Cheng) have led to collaborations with the Ernst Lab (Artinger et al PNAS, 2013) and the Whitfield lab (Cheng et al PlosGenetics, 2013) to reveal transcriptional factor networks underlying cancers under investigation.
A very significant body of basic to translational work has come from interprogrammatic collaborations between Dragnev, Dmitrovsky, Ahmed, DiRenzo and Memoli. Initially this work focused on animal models of lung cancer in which cyclin E was over-expressed and/or resistant to degradation. From this work, several mechanistic insights and avenues for therapy were discovered. Significantly, this work has extended into the clinic through work of Dr. Dragnev with input by Dr. Memoli (Ma et al, 2013), who showed that bexarotene could target cyclinD for degradation and, in conjunction with the EGFR inhibitor erlotinib, potentially could synergistically act to reduce cyclinD and cell survival.
2012 Selected Scientific Accomplishments
- Discovery of a new modulator of Wnt pathway signaling related to a molecule affected in myotonic dystrophy patients; this finding represents a new molecular target to influence Wnt-signaling in cancer (Xin N, et al., 2011).
- Xin N, Benchabane H, Tian A, Nguyen K, Klofas L, Ahmed Y (2011). Erect Wing facilitates context-dependent Wnt/Wingless signaling by recruiting the cell-specific Armadillo-TCF adaptor Earthbound to chromatin. Development 138(22):4955-4967. PMC3201663
- Identification of molecules and processes governing the polarity of cell division (Anker JF, et al., 2011).
- Anker JF, Gladfelter AS (2011). Axl2 integrates polarity establishment, maintenance, and environmental stress response in the filamentous fungus Ashbya gossypii. Eukaryot Cell 10(12):1679-1693. PMC3232731
- Discovery of a p53-Id2 tumor suppressor pathway in neural progenitor cells (Paollela BR, et al., 2012).
- Paolella BR, Havrda MC, Mantani A, Wray CM, Zhang Z, Israel MA (2011). p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells. Stem Cells 29(7):1090-1101.
- Development of a microRNA approach to reprogram dendritic cells to combat ovarian cancer (Cubillos-Ruiz JR, et al., 2012).
- Cubillos-Ruiz JR, Baird JR, Tesone AJ, Rutkowski MR, Scarlett UK, Camposeco-Jacobs AL, Anadon-Arnillas J, Harwood NM, Korc M, Fiering SN, Sempere LF, Conejo-Garcia JR (2012). Reprogramming tumor-associated dendritic cells in vivo using microRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res 72(7):1683-1693. PMC3319850
- Inter-programmatic work elucidating a retinoic acid-dependent step in the effector T cell and anti-tumor cytolytic T cell differentiation process (Guo Y, et al., 2012 and Piño-Lagos, et al., 2012).
- Pino-Lagos K, Guo Y, Brown C, Alexander MP, Elgueta R, Bennett KA, De Vries V, Nowak E, Blomhoff R, Sockanathan S, Chandraratna RA, Dmitrovsky E, Noelle RJ (2011). A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J Exp Med 208(9):1767-1775. PMC3171100
- Discovery of a role for Mad2 in stabilizing kinetochore-microtubule attachments in mitosis (Kabeche L, et al., 2012).
- Kabeche L, Compton DA (2012). Checkpoint-independent stabilization of kinetochoremicrotubule attachments by Mad2 in human cells. Curr Biol 22(7):638-644. PMC3326208
- Elucidation of a Myc-HIF1 pathway in cancer (Doe M, et al., 2012)
- Doe MR, Ascano JM, Kaur M, Cole MD (2012). Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res 72(4):949-957. PMC3288382 [Available on 2013/2/15]
- Inter-programmatic study resulting in the identification of UBP43 as an anti-cancer target (Guo Y, et al., 2012).
- Guo Y, Chinyengetere F, Dolinko AV, Lopez-Aguiar A, Lu Y, Galimberti F, Ma T, Feng Q, Sekula D, Freemantle SJ, Andrew AS, Memoli VA, Dmitrovsky E (2012, In press). Evidence for the Ubiquitin Protease UBP43 as an antineoplastic target. Mol Cancer Ther
- Collaborative discovery of a Polo-like-kinase mechanism to ensure chromosome segregation (Hood EA, et al., 2012).
- Hood EA, Kettenbach AN, Gerber SA, Compton DA (2012). Plk1 regulates the kinesin-13 protein Kif2b to promote faithful chromosome segregation. Mol Biol Cell 23(12):2264-2274. PMC Journal - In Process