Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue

Ciavarella, Sabino; Vegliante, Mariella; Fabbri, Marco; Summa, Simona De; Melle, Federica; Motta, Giovanna; Iuliis, Vincenzo De; Opinto, Giuseppina; Enjuanes, Anna; Rega, S; Gulino, Alessandro; Agostinelli, Claudio; Scattone, Anna; Tommasi, Stefania; Mangia, A.; Mele, Fabio; Simone, G.; Zito, Alfredo; Ingravallo, Giuseppe; Vitolo, Umberto; Chiappella, Annalisa; Tarella, Corrado; Gianni, Alessandro M.; Zinzani, P.; Casadei, Beatrice; Derenzini, Enrico; Loseto, Giacomo; Pileri, Alessandro; Tabanelli, Valentina; Fiori, Stefano; Rivas‐Delgado, Alfredo; López‐Guillermo, Armando; Venesio, Tiziana; Sapino, Anna; Campo, Elı́as; Tripodo, Claudio; Guarini, Attilio; Pileri, Stefano

doi:10.1093/annonc/mdz386

Cited by 40 publications

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“…For CIBERSORT 18 analyses, we created a customized signature matrix as previously reported. 7 Briefly, we used GEP from 24 different purified cell types collected from published datasets, to generate a microenvironment matrix specific for DLBCL. 7 The customized signature featuring 990 genes characteristic of tumor samples of both ABC and GCB COO categories, immune cells and stromal compartment, was applied to the 137 DLBCLs from Chapuy et al 4 The 137 cases were divided into two groups according to the median value of SPARC transcript expression from quantile normalized and log2 transformed gene expression measurements.…”

Section: Gene Set Enrichment Analysis Hierarchical Clustering and Cmentioning

confidence: 99%

“…[4][5] In the attempt to deconvolve the DLBCL complexity, the nature of associated stromal microenvironment has been investigated, revealing several layers of complexity in the stromal microenvironment, some of which associated with the COO, others providing further diversification. [6][7] From the seminal studies by the Staudt's group, a prognostic significance of the DLBCL-associated stromal microenvironment clearly emerged, which identified among the major determinants the matricellular protein SPARC, by the authors associated with tumor-infiltrating macrophages. 6,8 Indeed, SPARC consistently emerged as the fronting gene of prognostically relevant microenvironment-related signatures in DLBCL, [6][7]9 being low SPARC levels associated with poor prognosis in immuno-chemotherapy-treated DLBCL patients.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7] From the seminal studies by the Staudt's group, a prognostic significance of the DLBCL-associated stromal microenvironment clearly emerged, which identified among the major determinants the matricellular protein SPARC, by the authors associated with tumor-infiltrating macrophages. 6,8 Indeed, SPARC consistently emerged as the fronting gene of prognostically relevant microenvironment-related signatures in DLBCL, [6][7]9 being low SPARC levels associated with poor prognosis in immuno-chemotherapy-treated DLBCL patients. Our group has previously demonstrated that Sparc is a major stromal factor supporting bone marrow (BM) B lymphopoiesis and secondary lymphoid organ (SLO) function influencing the mesenchymal architecture of the GC.…”

Section: Introductionmentioning

confidence: 99%

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

Sangaletti¹,

Iannelli

Zanardi

et al. 2020

Preprint

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Word Count: 194 Text Word Count: 5649 Figures: 5 Supplemental Figures: 4 Supplemental Tables: 7 References: 48 2 KEY POINTS 1) Diversified stromal adaptations of infiltrated tissues shape DLBCL intra-tumor heterogeneity regulating transcriptional/phenotypic features 2) Stromal Sparc, which endorses prognostic significance in DLBCL, tunes the immune pressure exerted on lymphoma cells by the microenvironment ABSTRACT Intra-tumor heterogeneity in lymphoid malignancies is articulated around several fundamentals, encompassing selection of genetic subclonal events and epigenetic regulation of transcriptional programs. Clonally-related neoplastic cell populations are unsteadily subjected to immune editing and metabolic adaptations within different tissue microenvironments. How tissue-intrinsic mesenchymal determinants impact on the diversification of aggressive lymphomas is still unknown.In this study we adopted the established A20 line-based model of Diffuse Large B-cell Lymphoma (DLBCL), to investigate the intra-tumor heterogeneity associated with the infiltration of different tissue microenvironments and the specific mesenchymal modifications that characterize stromal adaptation to lymphoma seeding. Combining in situ quantitative immunophenotypical analyses and RNA sequencing, 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 determinant endowed with a strong prognostic significance in human DLBCL, we demonstrated a different immune imprint on A20 cells related to stromal Sparc proficiency. The study provides the first evidence of human DLBCL intra-lesional heterogeneity arising from diversified mesenchymal contextures and impacting on MYC expression, advancing the challenge for resolving intra-tumor heterogeneity probing stromal/immune interfaces.

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Section: Gene Set Enrichment Analysis Hierarchical Clustering and Cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sangaletti¹,

Iannelli

Zanardi

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…2,3 Further, gene expression profiling studies have shown that expression signatures of non-malignant cells in the tumor microenvironment have strong impact on survival in patients with Hodgkin lymphoma, FL, and diffuse large B-cell lymphoma (DLBCL). [4][5][6] In addition, candidate gene and genome-wide studies have found associations between germline polymorphisms and survival in Hodgkin lymphoma, CLL, FL, DLBCL, and multiple myeloma. [7][8][9][10][11][12][13] If the survival of lymphoid malignancies is, at least in part, dependent on germline genetic variation and normal cell function, [2][3][4][5][6] a concordance in survival among first-degree relatives diagnosed with lymphoid malignancies would be expected.…”

Section: Introductionmentioning

confidence: 99%

Concordance in survival among first‐degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia

Baecklund

Ekberg

Rosenquist

et al. 2020

European J of Haematology

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“…Defective sparc expression has been functionally linked with the induction of an inflammatory IFN type I related signature in myeloid cells, while sparc overexpression has been associated with the preferential recruitment of myeloid cells with suppressive function in lymphoid, myeloid, and solid malignancies [10][11][12]. Interestingly, the relative ex-pression levels of SPARC have been shown to endorse a strong prognostic significance in DLBCL as part of a microenvironment signature [13][14]. The additional level of complexity induced by the topography of the stromal architecture may thus affect the biological activity of the associated immune microenvironment, also casting an influence over relevant molecular programs intrinsic to the malignant cells, such as mechanosensing and activation of DNA damage checkpoints that are conditioned by ECM stiffness [15].…”

mentioning

confidence: 99%

Heterogeneity Fair: Commentary to Menter and Tzankov “Lymphomas and Their Microenvironment: A Multifaceted Relationship”

Tripodo

2020

Pathobiology

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The relevance of the tumor microenvironment in lymphomas is elegantly depicted and discussed in the review article by Thomas Menter and Alexandar Tzankov, published in December 2019 [1]. Most of the influence cast on malignant clones by the tumor-associated microenvironment (TME) stems from the direct activity of immune cells, which are the primary components of the TME in most malignancies, and by the well-represented, yet poorly characterized constellation of mesenchymal elements. Immune cells of the TME are intimately involved in an "arm wrestling" between anti-tumor immune responses and orchestration of immune escape-promoting conditions. In their review, the authors decline the diversified nature of immune players populating the TME of classic Hodgkin lymphoma, non-Hodgkin low-and highgrade B-cell lymphomas, and peripheral T-cell lymphomas, focusing on the multifarious network of cytokines, chemokines, and growth factors that dynamically influence the malignant clone proliferative and survival dynamics and/or reshape the surrounding tissue microarchitecture in favor of a tumor-promoting cell niche.Although the cellular immune and mesenchymal players taking part to the instruction of a tumor-supportive microenvironment in lymphomas predominantly display the same phenotypes and functional activation states of those populating the TME of epithelial cancers (e.g., different subsets of effector and regulatory T cells; tumorassociated macrophages, cancer-associated fibroblasts), a further level of complexity has to be attributed to the lymphoma TME, which is intrinsic to the lymphoid nature of the malignant clones. Apart from the special position of classic Hodgkin lymphoma with very complex TME interactions and dependence as comprehensively summarized by Menter and Tzankov [1], lymphomatous clones show phenotypic and functional hallmarks of mature lymphocytes, which for most subtypes allow their characterization as malignant proliferations of elements normally populating specific immune contextures, such as the germinal center (GC), the mantle or marginal zones, or mucosal epithelial-immune interfaces [2]. This evidence implies that the TME associated with lymphomatous clones is subjected to functional polarization spurs

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Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue

Cited by 40 publications

References 0 publications

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

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

Concordance in survival among first‐degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia

Heterogeneity Fair: Commentary to Menter and Tzankov “Lymphomas and Their Microenvironment: A Multifaceted Relationship”

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