title: Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells.
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 (αvβ3 and α4β1) 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.
authors.affiliation: Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Ye F
authors.initials: YF
authors.lastname: Tian
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Haelee
authors.initials: H
authors.lastname: Ahn
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Schneider
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Roman-Gonzalez
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA. Electronic address: as2833@cornell.edu.
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009940:Organoids / Q000737:chemistry; D014066:Palatine Tonsil / Q000378:metabolism; D000077767:Panobinostat; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D056572:Histone Deacetylase Inhibitors; D020100:Hydrogels; D006877:Hydroxamic Acids; D007211:Indoles; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D000077767:Panobinostat
keywords: B cell; Hydrogels; Integrins; Lymphoma; Organoids; Panobinostat; T cell