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RESEARCH PRODUCT

Intra-tumour heterogeneity of diffuse large B-cell lymphoma involves the induction of diversified stroma-tumour interfaces

Maurilio PonzoniCesare ValentiClaudia ChiodoniSabina SangalettiMaria Carmela VeglianteLaura BottiClaudio TripodoCeleste RizzelloMario P. ColomboArianna Di NapoliPaola PortararoDavide VaccaFederica PisatiAlessandro GulinoFederica ZanardiValeria CancilaFabio Iannelli

subject

0301 basic medicinediffuse large B-cell lymphoma; digital spatial profiling; intra-tumour heterogeneity; microenvironment; SPARClcsh:MedicineMice0302 clinical medicineimmune system diseaseshemic and lymphatic diseasesTumor MicroenvironmentIn Situ Hybridizationlcsh:R5-920Matricellular proteinGeneral MedicineDiffuse large B-cell lymphomaPrognosisGene Expression Regulation NeoplasticPhenotype030220 oncology & carcinogenesisLymphoma Large B-Cell Diffuselcsh:Medicine (General)Research PaperStromal cellMicroenvironmentTumour heterogeneityBiologySettore MED/08 - Anatomia PatologicaModels BiologicalGeneral Biochemistry Genetics and Molecular BiologyImmunophenotypingGenetic Heterogeneity03 medical and health sciencesImmune systemCell Line TumorBiomarkers TumormedicineAnimalsHumansEpigeneticsSequence Analysis RNAGene Expression Profilinglcsh:RMesenchymal stem cellComputational BiologySPARCDigital spatial profilingmedicine.diseaseIntra-tumour heterogeneityDisease Models Animal030104 developmental biologyCancer researchNeoplastic cellStromal CellsTranscriptomeDiffuse large B-cell lymphoma

description

Abstract Background 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. Methods Combining in situ quantitative immunophenotypical analyses and RNA sequencing 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. Furthermore, we characterized features of lymphoma-associated stromatogenesis in human DLBCL samples using Digital Spatial Profiling, and established their relationship with prognostically relevant variables, such as MYC. Findings 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. Through Digital Spatial Profiling of 87 immune and stromal genes on human nodal DLBCL regions characterized by different mesenchymal composition, we demonstrate intra-lesional heterogeneity arising from diversified mesenchymal contextures and impacting on the stromal and immune milieu. Interpretation Our study provides experimental evidence that stromal microenvironment generates topological determinants of intra-tumour heterogeneity in DLBCL involving key transcriptional pathways such as Myc expression, damage response programs and immune checkpoints. Funding This study has been supported by the Italian Foundation for Cancer Research (AIRC) (grants 15999 and 22145 to C. Tripodo) and by the University of Palermo.

yearjournalcountryeditionlanguage
2020-11-01
10.1016/j.ebiom.2020.103055http://hdl.handle.net/10447/468002