Thieblemont, C. | Search bioRxiv

bioRxiv2024

Spatial transcriptomics unveils immune cellular ecosystems associated with patient survival in diffuse large B-cell lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkins lymphoma for which current therapeutic strategies remain insufficient. The diffuse nature of DLBCL, lacking distinct tissue structures, represents a challenge to elucidate the cellular organization and interactions within the tumor microenvironment (TME). In this study, we applied spatial transcriptomics to identify spatially-resolved gene expression profiles in 10 DLBCL tissue samples, identifying distinct immune cell infiltration and colocalization patterns. These profiles were classified into six cellular ecosystems (Cell-Eco) that differ in cellular composition, functional patterns, and neighborhood characteristics. The spatially-resolved Cell-Eco signatures provided prognostic scores that stratified patients with different overall survival rates. We also found that C1q+ tumor-associated macrophages are the primary cells interacting with malignant B cells and influencing the spatial architecture of the TME. This study provides novel biological insights into the complexity of the TME in DLBCL and highlights the potential prognostic value of its spatial organization. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/613252v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@147a46eorg.highwire.dtl.DTLVardef@7c5236org.highwire.dtl.DTLVardef@1f99506org.highwire.dtl.DTLVardef@a6d271_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LISpatial transcriptomics classifies DLBCL tissues based on immune cell infiltration and colocalization patterns. C_LIO_LIDLBCL tumor microenvironment consists of cellular ecosystems (Cell-Eco) that differ in cellular composition, transcriptomic profiles and neighborhood characteristics. C_LIO_LISpatially-resolved Cell-Eco signatures stratify patients with different overall survival. C_LIO_LIC1q+ tumor-associated macrophages primarily interact with malignant B cells and contribute to the spatial organization of the tumor microenvironment. C_LI

immunology↗

bioRxiv2020

HSP90 facilitates oncogenic alterations of metabolism in B-cell lymphomas

HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here, we described a novel role of HSP90 in the cytosolic compartmentalization of metabolic pathways in proliferating cancer cells. We found that HSP90 assists in the organization of metabolic enzymes into non-membrane-bound functional compartments termed metabosomes. Under experimental conditions that conserved the cellular proteostasis, we demonstrated that the compartmentalizing activity of HSP90 is critical to sustain the coordinated synthesis of multiple metabolites required for energy production, maintenance of the cellular biomass and secretion of immunometabolites. Conversely, inhibition of the nucleating capacity of HSP90 modified the topology of cytosolic metabosomes before protein degradation was apparent decreasing the efficiency of MYC-driven metabolic pathways. Inhibition of HSP90 decreases cancer metabolism in B-cell lymphoma cells and patients providing a novel mechanism of activity for this class of drugs.

cancer biology↗