Article: Tian, YF; Ahn, H; Schneider, RS; Yang, SN; Roman-Gonzalez, L; Melnick, AM; Cerchietti, L; Singh, A; (2015) “Integrin-specific Hydrogels as Adaptable Tumor Organoids for Malignant B and T Cells”, Biomaterials, 73: 110-119
Abstract: Non-Hodgkin lymphomas are a heterogeneous group of lymphoproliferative disorders of B and T cell origin that are treated with chemotherapy drugs with variable success rate that has virtually not changed over decades. Although new classes of chemotherapy-free epigenetic and metabolic drugs have emerged, durable responses to these conventional and new therapies are achieved in a fraction of cancer patients, with many individuals experiencing resistance to the drugs. The paucity in our understanding of what regulates the drug resistance phenotype and establishing a predictive indicator is, in great part, due to the lack of adequate ex vivo lymphoma models to accurately study the effect of microenvironmental cues in which malignant B and T cell lymphoma cells arise and reside. Unlike many other tumors, lymphomas have been neglected from biomaterials-based microenvironment engineering standpoint. In this study, we demonstrate that B and T cell lymphomas have different pro-survival integrin signaling requirements (alpha v beta 3 and alpha 4 beta 1) and the presence of supporting follicular dendritic cells are critical for enhanced proliferation in three-dimensional (3D) microenvironments. We engineered adaptable 3D tumor organoids presenting adhesive peptides with distinct integrin specificities to B and T cell lymphoma cells that resulted in enhanced proliferation, clustering, and drug resistance to the chemotherapeutics and a new class of histone deacetylase inhibitor (HDACi), Panobinostat.
In Diffuse Large B cell Lymphomas, the 3D microenvironment upregulated the expression level of B cell receptor (BCR), which supported the survival of B cell lymphomas through a tyrosine kinase Syk in the upstream BCR pathway. Our integrin specific ligand functionalized 3D organoids mimic a lymphoid neoplasm-like heterogeneous microenvironment that could, in the long term, change the understanding of the initiation and progression of hematological tumors, allow primary biospecimen analysis, provide prognostic values, and importantly, allow a faster and more rational screening and translation of therapeutic regimens. (C)
2015 Elsevier Ltd. All rights reserved.
Funding Acknowledgement: National Institutes of Health [1R21CA185236-01]; Cornell University; Weill Cornell Medical College Seed Grant Program; Cornell University’s Engineering Learning Initiative Grant
Funding Text: The authors acknowledge financial support from the National Institutes of Health (1R21CA185236-01), the Cornell University and Weill Cornell Medical College Seed Grant Program, and Cornell University’s Engineering Learning Initiative Grant. The authors thank Cornell University Biotechnology Resource Center (and NIH S10RR025502) for the use of microscopy resources. The authors thank Giorgio Inghirami at Weill Cornell Medical College of Cornell University for providing insights into lymphoma studies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.