Welcome to Dana-Farber's Research News
January 15, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
July 15, 2021
Blood
Two to Tango! IL-13 and TGF-b Drive Myelofibrosis
Jutzi JS, Mullally A
In this issue of Blood, Melo-Cardenas et al explore the role of interleukin-13 (IL-13)/IL-4 signaling in myelofibrosis as an important pathway driving fibrotic progression through megakaryocyte expansion and increased transforming growth factor-? (TGF-?) production.
Cancer Discovery
A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas
Cervia LD, Shibue T, Borah AA, Gaeta B, He L, Leung L, Li N, Moyer SM, Shim BH, Dumont N, Gonzalez A, Kazachkova M, Dempster JM, Krill-Burger JM, Piccioni F, Udeshi ND, Olive ME, Carr SA, Root DE, McFarland JM, Vazquez F, Hahn WC
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
Journal of the National Cancer Institute
Survival in Male Breast Cancer Over the Past Three Decades
Leone JP, Freedman RA, Tolaney SM, Winer EP, Lin NU, Hassett MJ
Background: Breast cancer mortality in women has declined significantly over the past several years. In men, it is unclear whether survival has changed over time. We evaluated changes in breast cancer-specific survival (BCSS) and overall survival (OS) in male breast cancer (MaBC) over the past 3 decades.
Methods: We evaluated men diagnosed with breast cancer between 1988 and 2017, reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007 and 2008-2017. BCSS and OS were estimated by Kaplan-Meier and differences between groups were compared by log-rank test. Multivariable Cox regression evaluated the independent association of year of diagnosis with BCSS and OS. All tests were 2-sided.
Results: We included 8,481 men. Overall, BCSS at 5 years was 83.69%, 83.78% and 84.41% in groups 1988-1997, 1998-2007 and 2008-2017, respectively; P=.86. There was no significant difference in BCSS between the 3 groups within each stage of disease. Among all patients, OS at 5 years was 64.61%, 67.31% and 69.05% in groups 1988-1997, 1998-2007 and 2008-2017, respectively; P=.01. In adjusted Cox models, each additional year of diagnosis had no significant association with BCSS (hazard ratio, 1.00; 95% confidence interval: 0.99-1.01; P=.75), but there was significant improvement in OS (hazard ratio, 0.99; 95% CI: 0.98-0.99; P=.009).
Conclusion: Over the past 3 decades, there has been no significant improvement in BCSS in MaBC. Changes in OS over time are consistent with increasing life expectancy. Efforts to improve BCSS in MaBC are warranted.
Proceedings of the National Academy of Sciences of the U.S.A.
Discovery of Antibodies and Cognate Surface Targets for Ovarian Cancer by Surface Profiling
Schröfelbauer B, Kimes PK, Hauke P, Reid CE, Shao K, Hill SJ, Irizarry R, Hahn WC
Although antibodies targeting specific tumor-expressed antigens are the standard of care for some cancers, the identification of cancer-specific targets amenable to antibody binding has remained a bottleneck in development of new therapeutics. To overcome this challenge, we developed a high-throughput platform that allows for the unbiased, simultaneous discovery of antibodies and targets based on phenotypic binding profiles. Applying this platform to ovarian cancer, we identified a wide diversity of cancer targets including receptor tyrosine kinases, adhesion and migration proteins, proteases and proteins regulating angiogenesis in a single round of screening using genomics, flow cytometry, and mass spectrometry. In particular, we identified BCAM as a promising candidate for targeted therapy in high-grade serous ovarian cancers. More generally, this approach provides a rapid and flexible framework to identify cancer targets and antibodies.
Science
Epigenetic Clocks, Aging, and Cancer
Johnstone SE, Gladyshev VN, Aryee MJ, Bernstein BE
Cancer and aging are accompanied by stereotyped changes to the epigenetic landscape, including progressive loss of DNA methylation over gene-poor genomic regions. Global hypomethylation arises in cells that have undergone many divisions, likely owing to imperfect maintenance. Evidence suggests that global hypomethylation represents a “mitotic clock” that counts divisions in somatic cells and functions to restrain aging cells and limit malignant progression. Therapies that modulate the pace of methylation loss or eliminate hypomethylated cells could alleviate agingassociated diseases or cancers.
Abdominal Radiology
Glazer DI, Mayo-Smith WW, Brook OR, Shinagare AB, Blake MA
Biophysical Journal
Three-Phase DNA-Origami Stepper Mechanism Based on Multi-Leg Interactions
Kilwing L, Lill P, Nathwani B, Shih WM
Blood Advances
DeFilipp Z, Kim HT, Cutler C
Blood Advances
Patient Perspectives on Testing for Clonal Hematopoiesis of Indeterminate Potential
Sella T, Fell GG, Miller PG, Gibson CJ, Snow C, Peppercorn JM, Come SE, Frank E, Neuberg DS, Ebert BL, Partridge AH
Blood Cancer Journal
Aktas Samur A, Fulciniti M, Derebail S, Corre J, Anderson KC, Parmigiani G, Samur MK, Munshi NC
Cancer Research
Systematic Interrogation of Tumor Cell Resistance to CAR T Cell Therapy in Pancreatic Cancer
Hagel KR, Arafeh R, Gang S, Arnoff TE, Larson RC, Doench JG, Mathewson ND, Wucherpfennig KW, Maus MV, Hahn WC
Cancers
Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma
Huffman BM, Ellis H, Jordan AC, Freed-Pastor WA, Perez K, Rubinson DA, Sethi N, Singh H, Surana R, Wolpin BM, Aguirre AJ, Cleary JM
Cell Reports
The ADP-Ribose Hydrolase NUDT5 is Important for DNA Repair
Qi H, Price BD
Clinical Cancer Research
Chen EC, Gandler H, Tosic I, Fell GG, Pozdnyakova O, DeAngelo DJ, Galinsky I, Luskin MR, Wadleigh MS, Winer ES, Leonard R, de Jonge A, Neuberg D, Look AT, Stone RM, Garcia JS
International Journal of Cancer
Dysfunctions of Innate and Adaptive Immune Tumor Microenvironment in Waldenström Macroglobulinemia
Hunter ZR, Hideshima T, Flores L, Treon SP, Dorfman DM, Anderson KC, Jakubikova J
JCO Oncology Practice
Roberts DA, Faig J, Wischhusen J, Giordano S, Acharya U, Drews R, Dougherty D, Lathan C, Rangachari D
Leukemia Research
Raman HS, Kim SE, DeAngelo DJ, Stevenson KE, Neuberg D, Winer ES, Wadleigh M, Garcia JS, Kim AS, Stone RM, Ho VT, Luskin MR
Nature Nanotechnology
Multi-Micron Crisscross Structures Grown from DNA-Origami Slats
Wintersinger CM, Minev D, Ershova A, Sasaki HM, Gowri G, Berengut JF, Corea-Dilbert FE, Yin P, Shih WM
Neoplasia
Pediatric Low-Grade Glioma: Targeted Therapeutics and Clinical Trials in the Molecular Era
Liu KX, Haas-Kogan DA, Bandopadhayay P
Neuron
Qi L, Lin SH, Ma Q
Oncologist
McDermott D, Choueiri TK
Pediatric Blood and Cancer
Merz A, Das PJ, Avery M, Revette AC, Wolfe J, Feraco AM
Pediatric Blood and Cancer
Nekhlyudov L, Snow C, Knelson LP, Dibble KE, Partridge AH
STAR Protocols
Baldominos P, Barreiro O, von Andrian U, Montero-Llopis P, Agudo J
Transplantation and Cellular Therapy
Sannes T, Nelson AJ, Gray TF, Pozo-Kaderman C, Miran DM, Amonoo HL