Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Zavidij, Oksana; Haradhvala, Nicholas J.; Mouhieddine, Tarek H.; Sklavenitis-Pistofidis, Romanos; Agius, Michael P.; Cai, Shanshan; Reidy, Mairéad; Rahmat, Mahshid; Flaifel, Abdallah; Ferland, Benjamin; Park, Jihye; Manier, Salomon; Bustoros, Mark; Huynh, Daisy; Capelletti, Marzia; Berrios, Brianna; Liu, Chia-Jen; He, Meng Xiao; Braggio, Esteban; Fonseca, Rafaël; Maruvka, Yosef E.; Guerriero, Jennifer L.; Goldman, Melissa; Allen, Eliezer Van; McCarroll, Steven A.; Azzi, Jamil; Getz, Gad; Ghobrial, Irène M.

doi:10.1016/j.clml.2019.09.040

Cited by 51 publications

(103 citation statements)

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“…The distribution and phenotypic and behavioral features of the natural killer cells, cytotoxic and other T cells, monocytes, and macrophages play an essential role in the progression from premalignant MM to active disease. A precise understanding of these modifications will help to develop new therapeutic strategies as well as accurate patient stratification [ 44 ].…”

Section: Angiogenesis In MM Progressionmentioning

confidence: 99%

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

Ria

Melaccio

Racanelli

et al. 2020

JCM

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The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.

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Section: Angiogenesis In MM Progressionmentioning

confidence: 99%

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

Ria

Melaccio

Racanelli

et al. 2020

JCM

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“…However, the risk of infection decreased with the response to therapy, which suggests some immune reconstitution accompanies a lower burden of myeloma. In addition to progressive impairment of humoral immunity, changes across many cell types of the bone marrow immune microenvironment, including Natural Killer (NK), Dendritic, and T-cells, have been observed from MGUS, to SMM, and MM [ 69 ]. These observations support the concept that there is progressive immunoparesis that accompanies disease progression from MGUS to MM.…”

Section: Immunodeficiency In Mgusmentioning

confidence: 99%

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Lomas

Mouhieddine

Tahri

et al. 2020

Cancers

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Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.

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“…Others combined single cell RNA sequencing (scRNA-seq) with spatial transcriptomics to map and characterize the different cell populations in heterogeneous pancreatic tumors 39 . In multiple myeloma, spatial organization was inferred from scRNA-seq data, using a clustering-based approach, to characterize immunological alterations occurring in the tumor microenvironment during disease progression 40 . Similarly, a computational approach was used to infer spatial position probabilities for individual cells from scRNA-seq data, enabling the spatial reconstruction of single-cell gene expression 41 .…”

Section: Introductionmentioning

confidence: 99%

Spatial transcriptomics inferred from pathology whole-slide images links tumor heterogeneity to survival in breast and lung cancer

Levy-Jurgenson

Tekpli

Kristensen

et al. 2020

Sci Rep

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Digital analysis of pathology whole-slide images is fast becoming a game changer in cancer diagnosis and treatment. Specifically, deep learning methods have shown great potential to support pathology analysis, with recent studies identifying molecular traits that were not previously recognized in pathology H&E whole-slide images. Simultaneous to these developments, it is becoming increasingly evident that tumor heterogeneity is an important determinant of cancer prognosis and susceptibility to treatment, and should therefore play a role in the evolving practices of matching treatment protocols to patients. State of the art diagnostic procedures, however, do not provide automated methods for characterizing and/or quantifying tumor heterogeneity, certainly not in a spatial context. Further, existing methods for analyzing pathology whole-slide images from bulk measurements require many training samples and complex pipelines. Our work addresses these two challenges. First, we train deep learning models to spatially resolve bulk mRNA and miRNA expression levels on pathology whole-slide images (WSIs). Our models reach up to 0.95 AUC on held-out test sets from two cancer cohorts using a simple training pipeline and a small number of training samples. Using the inferred gene expression levels, we further develop a method to spatially characterize tumor heterogeneity. Specifically, we produce tumor molecular cartographies and heterogeneity maps of WSIs and formulate a heterogeneity index (HTI) that quantifies the level of heterogeneity within these maps. Applying our methods to breast and lung cancer slides, we show a significant statistical link between heterogeneity and survival. Our methods potentially open a new and accessible approach to investigating tumor heterogeneity and other spatial molecular properties and their link to clinical characteristics, including treatment susceptibility and survival.

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Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Cited by 51 publications

References 0 publications

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

Spatial transcriptomics inferred from pathology whole-slide images links tumor heterogeneity to survival in breast and lung cancer

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