Award Winner in the Young Investigator Category, 2017 Society for Biomaterials Annual Meeting and Exposition, Minneapolis, MN, April 05-08, 2017: Lymph node stiffness-mimicking hydrogels regulate human B-cell lymphoma growth and cell surface receptor expression in a molecular subtype-specific manner.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, with multiple molecular subtypes. The activated B-cell-like DLBCL subtype accounts for roughly one-third of all the cases and has an inferior prognosis. There is a need to develop better class of therapeutics that could target molecular pathways in resistant DLBCLs; however, this requires DLBCLs to be studied in representative tumor microenvironments. The pathogenesis and progression of lymphoma has been mostly studied from the point of view of genetic alterations and intracellular pathway dysregulation. By comparison, the importance of lymphoma microenvironment in which these malignant cells arise and reside has not been studied in as much detail. We have recently elucidated the role of integrin signaling in lymphomas and demonstrated that inhibition of integrin-ligand interactions abrogated the proliferation of malignant cells in vitro and in patient-derived xenograft. Here we demonstrate the role of lymph node tissue stiffness on DLBCL in a B-cell molecular subtype specific manner. We engineered tunable bioartificial hydrogels that mimicked the stiffness of healthy and neoplastic lymph nodes of a transgenic mouse model and primary human lymphoma tumors. Our results demonstrate that molecularly diverse DLBCLs grow differentially in soft and high stiffness microenvironments, which further modulates the integrin and B-cell receptor expression level as well as response to therapeutics. We anticipate that our findings will be broadly useful to study lymphoma biology and discover new class of therapeutics that target B-cell tumors in physical environments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1833-1844, 2017.
Sibley School of Mechanical and Aerospace Engineering, College of Engineering, Cornell University, Ithaca, New York.
F N U
FNU
Apoorva
Sibley School of Mechanical and Aerospace Engineering, College of Engineering, Cornell University, Ithaca, New York.
Ye F
YF
Tian
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Timothy M
TM
Pierpont
Meinig School of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, New York.
David M
DM
Bassen
Division of Hematology and Medical Oncology, Weill Cornell Medical College of Cornell University, New York, New York.
Leandro
L
Cerchietti
Meinig School of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, New York.
Jonathan T
JT
Butcher
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Robert S
RS
Weiss
Sibley School of Mechanical and Aerospace Engineering, College of Engineering, Cornell University, Ithaca, New York.|Meinig School of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, New York.
Ankur
A
Singh
D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D016023:Integrins / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015398:Signal Transduction
D020100:Hydrogels; D016023:Integrins; D009363:Neoplasm Proteins
B-cell receptor; DLBCL; biomechanics; chemoresistance; contractility; extracellular matrix; germinal center; integrin; organoids; tissue stiffness