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

Abstract

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.

Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment

“…1236–1241 This is because these factors (particularly mechanical cues) have been shown to play vital roles in immune cell migration and activation, lymphoid tissue development and function, and immune-related disease progression such as malignant transformation. 1111,1242–1244…”

Perspective: Biophysical regulation of cancerous and normal blood cell lineages in hematopoietic malignancies

“…A recent study demonstrates that some AML cells, including those harboring a MLL-AF9 mutation, show a biphasic growth pattern as a function of matrix stiffness due to an autocrine inhibitory mechanism 62 . The biphasic growth as a function of matrix stiffness has also been observed in some lymphoma cells 63 . Interestingly, this kind of growth pattern is reminescent of early normal hematopoiesis where dormant HSCs rarely proliferate, while active self-renewing HSCs are found near the softer perivascular niche, and differentiated blood cells no longer undergo active proliferation as they exit the marrow into the blood 64 .…”

Hydrogels for Engineering the Immune System

“…n = 3, * p < 0.05) Reproduced with permission. [ 54 ] Copyright 2017, Wiley. E) CCL21‐loaded 3D polyethylene glycol/heparin hydrogels promoted differentiation of naïve T cells into central memory and effector memory T cells for adoptive cell therapy.…”