The Tumor Microenvironment of DLBCL in the Computational Era

Opinto, Giuseppina; Vegliante, Maria Carmela; Negri, Antonio; Skrypets, Tetiana; Loseto, Giacomo; Pileri, Stefano; Guarini, Attilio; Ciavarella, Sabino

doi:10.3389/fonc.2020.00351

Cited by 27 publications

(23 citation statements)

References 55 publications

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“…Hodgkin lymphoma (HL) is a hematopoietic neoplasm generated from B-cells, affecting secondary lymphoid tissues such as lymph nodes and spleen. Despite recent advances in the biological knowledge and targeted therapy, almost a quarter of lymphoma patients relapse, due to the complex interactions between residual neoplastic cells and the microenvironment, and the emergence of metabolic adaptive responses which mediate drug resistance and contribute to clonal selection, at different times and in the different sites of the same patient (75)(76)(77)(78)(79).…”

Section: Increased Ox-phos In Hodgkin Lymphoma Is Associated To Revermentioning

confidence: 99%

“…Non-Hodgkin lymphoma (NHL) includes quite heterogeneous group of blood neoplasms that differ for metabolism, cell of origin, clinical course, and response to treatment (79,(100)(101)(102). The relationship between metabolic pathway differences and drug resistance has led to an increasing interest in metabolic mechanisms important for lymphoma cells surviving.…”

Section: Ox-phos Identifies Metabolic Subtypes Of B-cell Non-hodgkin mentioning

confidence: 99%

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Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.

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Section: Increased Ox-phos In Hodgkin Lymphoma Is Associated To Revermentioning

confidence: 99%

Section: Ox-phos Identifies Metabolic Subtypes Of B-cell Non-hodgkin mentioning

confidence: 99%

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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“… 17 Due to its high heterogeneity, DLBCL can be divided into many subtypes, and different histological types have different responses to treatment. 18 The present study firstly identified an increase of lncRNA SBF2-AS1 in DLBCL tissues. And functional experiments showed that silencing SBF2-AS1 inhibited DLBCL cell growth.…”

Section: Discussionmentioning

confidence: 62%

LncRNA SBF2-AS1 Promotes Diffuse Large B-Cell Lymphoma Growth by Regulating FGFR2 via Sponging miR-494-3p

Fu¹,

Liu²

2021

CMAR

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Purpose: Currently, there is no efficient and feasible method for diffuse large B-cell lymphoma (DLBCL) in clinical practice, and the main reason is the unclear pathogenesis of DLBCL, which leads to a high fatality rate of DLBCL. Methods: Therefore, it is meaningful to explore the molecular mechanism of DLBCL and find a targeted therapeutic approach from the molecular level. Results: Long non-coding RNA (lncRNA) SBF2-AS1 was highly expressed in DLBCL tissues and cell lines. Silencing of SBF2-AS1 inhibited the viability and growth of OCI-LY-3 cells. Furthermore, SBF2-AS1 acted as a sponge of miR-494-3p and inhibited its expression. And miR-494-3p directly targeted FGFR2. Functionally, forced expression of miR-494-3p or knockdown of FGFR2 removed the promoted effects of lncRNA SBF2-AS1 on DLBCL development. In vivo tumorigenesis experiments indicated SBF2-AS1 accelerated tumor growth via miR-494-3p/FGFR2 axis. Conclusion:Our study revealed that SBF2-AS1 promoted the growth of DLBCL, which were mediated by miR-494-3p/FGFR2 axis.

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“…The DLBCL TME is complex, with tumor cells interacting with stroma and immune cells ( 32 ). To assess TME cellular architecture in more detail we constructed tissue microarrays (TMA) from archival ABC and GCB DLBCL diagnostic biopsy samples and applied IHC for appropriate cell-specific targets.…”

Section: Resultsmentioning

confidence: 99%

Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy

et al. 2021

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Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.

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The Tumor Microenvironment of DLBCL in the Computational Era

Cited by 27 publications

References 55 publications

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

LncRNA SBF2-AS1 Promotes Diffuse Large B-Cell Lymphoma Growth by Regulating FGFR2 via Sponging miR-494-3p

Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy

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