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. 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.

淋巴系恶性肿瘤的肿瘤内异质性（Intra-tumour heterogeneity）涵盖遗传事件的筛选与转录程序的表观遗传调控。克隆相关的肿瘤细胞群在不同组织微环境中会经历动态变化的免疫编辑与代谢适应过程。目前，组织特异性间充质细胞如何影响侵袭性淋巴瘤克隆的多样化进程仍未明确。本研究针对A20弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, DLBCL）细胞在不同组织微环境中的定植情况，探究了其肿瘤内异质性以及与之相关的特异性间充质改变。研究发现，组织微环境可对A20细胞的转录谱产生显著影响，同时还会调控Myc基因与DNA损伤应答程序。我们将研究拓展至缺失基质细胞蛋白SPARC（matricellular protein SPARC）的小鼠——SPARC是人类DLBCL的间质预后因子——并证实，根据间质Sparc的功能完整性，A20细胞会呈现出差异化的免疫印记。将A20淋巴瘤细胞接种至野生型（wild type, WT）或Sparc基因敲除（Sparc-/-）受体小鼠体内，接种5周后，我们从每种基因型的5只小鼠的骨髓、脾脏与肝脏中分离肿瘤细胞，并开展RNA测序（RNA-seq）转录组分析。