Intra-tumour heterogeneity of Diffuse Large B-cell Lymphoma involves the induction of diversified stroma-tumour interfaces

Intra-tumour heterogeneity in lymphoid malignancies encompasses selection of genetic events and epigenetic regulation of transcriptional programs. Clonal-related neoplastic cell populations are unsteadily subjected to immune editing and metabolic adaptations within different tissue microenvironments. How tissue-specific mesenchymal cells impact on the diversification of aggressive lymphoma clones is still unknown. We investigated the intra-tumour heterogeneity and the specific mesenchymal modifications that are associated with A20 diffuse large B-cell lymphoma (DLBCL) cells seeding of different tissue microenvironments. We found that the tissue microenvironment casts a relevant influence over A20 transcriptional landscape also impacting on Myc and DNA damage response programs. Extending the investigation to mice deficient for the matricellular protein SPARC, a stromal prognostic factor in human DLBCL, we demonstrated a different immune imprint on A20 cells according to stromal Sparc proficiency. Overall design: A20 lymphoma cells were injected into WT or Sparc-/- recipent mice. Following 5 weeks of injection tumor cells were isolated from the bone marrow, spleen and liver of 5 mice per genotype and subjected to RNA-seq profiling.