Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells

Biomaterials. 2015 Dec:73:110-9. doi: 10.1016/j.biomaterials.2015.09.007. Epub 2015 Sep 11.

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.

Keywords: B cell; Hydrogels; Integrins; Lymphoma; Organoids; Panobinostat; T cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • Biocompatible Materials / chemistry
  • Cell Proliferation
  • Coculture Techniques
  • Dendritic Cells / cytology
  • Histone Deacetylase Inhibitors / chemistry
  • Humans
  • Hydrogels / chemistry*
  • Hydroxamic Acids / chemistry
  • Indoles / chemistry
  • Integrin alpha4beta1 / metabolism
  • Integrin alphaVbeta3 / metabolism
  • Integrins / metabolism*
  • Ligands
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, Non-Hodgkin / metabolism*
  • Lymphoma, T-Cell / metabolism*
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Organoids / chemistry
  • Palatine Tonsil / metabolism
  • Panobinostat
  • Receptors, Antigen, B-Cell / chemistry
  • Signal Transduction
  • Tissue Engineering / methods
  • Up-Regulation

Substances

  • Antineoplastic Agents
  • Biocompatible Materials
  • Histone Deacetylase Inhibitors
  • Hydrogels
  • Hydroxamic Acids
  • Indoles
  • Integrin alpha4beta1
  • Integrin alphaVbeta3
  • Integrins
  • Ligands
  • Receptors, Antigen, B-Cell
  • Panobinostat