Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia

Heydebrand, Franziska von; Fuchs, Maximilian; Kunz, Meik; Voelkl, Simon; Kremer, Anita N.; Oostendorp, Robert A.J.; Wilke, Jochen; Leitges, Michael; Egle, Alexander; Mackensen, Andréas; Lutzny‐Geier, Gloria

doi:10.1002/stem.3352

Cited by 6 publications

(5 citation statements)

References 52 publications

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“…In CLL, protein kinases in the stroma such as PKCβ promote disease progression and influence therapy response 6 . Besides inducing metabolic changes, PKCβ activates NFκΒ and TFEB in stromal cells, thereby regulating proteins involved in CLL contact like VCAM1 30,55 . We similarly demonstrated that stromal LYN stimulated comparable inflammatory signaling pathways and sustained CLL survival in a contact-dependent manner, agreeing with previous studies that direct cell contact was required for the feeding of CLL cells 30,[56][57][58] .…”

Section: Discussionmentioning

confidence: 99%

LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

et al. 2023

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Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype.

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Section: Discussionmentioning

confidence: 99%

LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

et al. 2023

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“…Concurrent administration of 2-deoxy-glucose and IACS-010759 suppressed this compensatory glycolysis and induced CLL cells apoptosis ( Vangapandu et al, 2018 ). Protein kinase C-β (PKCβ) also plays a critical role in the BM stroma and CLL cell interaction, where they provide a cancer-supportive inflammatory microenvironment ( vom Stein et al, 2023 ), chemoresistance ( Amigo-Jiménez et al, 2015 ), and establish metabolic symbiosis ( von Heydebrand et al, 2021 ). An interaction through PKCβ reduced glycolysis and insulin signaling in the BM-stromal cells and simultaneously increased the glycolysis/lactate production in CLL cells.…”

Section: Role Of Mscs and Their Adipocytic Lineage In Hematological M...mentioning

confidence: 99%

Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis

Singh,

Prasad,

Cancelas

2023

Front. Cell Dev. Biol.

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Hematopoietic stem cell (HSC) transplantation-based treatments are in different phases of clinical development, ranging from current therapies to a promise in the repair and regeneration of diseased tissues and organs. Mesenchymal stromal/stem cells (MSCs), which are fibroblast-like heterogeneous progenitors with multilineage differentiation (osteogenic, chondrogenic, and adipogenic) and self-renewal potential, and exist in the bone marrow (BM), adipose, and synovium, among other tissues, represent one of the most widely used sources of stem cells in regenerative medicine. MSCs derived from bone marrow (BM-MSCs) exhibit a variety of traits, including the potential to drive HSC fate and anti-inflammatory and immunosuppressive capabilities via paracrine activities and interactions with the innate and adaptive immune systems. The role of BM-MSC-derived adipocytes is more controversial and may act as positive or negative regulators of benign or malignant hematopoiesis based on their anatomical location and functional crosstalk with surrounding cells in the BM microenvironment. This review highlights the most recent clinical and pre-clinical findings on how BM-MSCs interact with the surrounding HSCs, progenitors, and immune cells, and address some recent insights on the mechanisms that mediate MSCs and adipocyte metabolic control through a metabolic crosstalk between BM microenvironment cells and intercellular mitochondrial transfer in normal and malignant hematopoiesis.

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“…Corroborating this scenario, CLL cells isolated from blood samples are non-dividing, although their metabolism is still active [147]. In this context, Jitschin and colleagues reported that CLL cells acquire an increased glucose dependency upon contact with stromal cells [146], in turn promoting glucose uptake in CLL cells by decreasing mitochondrial stress and apoptosis [148]. However, this outcome is still debated.…”

Section: Role Of Mscs In In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

“…Therefore, as also described, is possible that leukemic cells modify MSCs' metabolism to satisfy their energy demand. Recently, it was reported that after contact with CLL cells, MSCs switch their metabolism toward OXPHOS with consequent lower glucose usage, which might be an advantage for CLL survival [148].…”

Section: Role Of Mscs In In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

Giallongo,

Duminuco,

Dulcamare

et al. 2023

Biomolecules

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Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Once a malignant event occurs, the BMME acquires cellular, molecular, and epigenetic abnormalities affecting tumor growth and progression. In this context, MSC behavior is affected by signals coming from cancer cells. Furthermore, it has been shown that stromal cells themselves play a major role in several hematological malignancies’ pathogenesis. This bidirectional crosstalk creates a functional tumor niche unit wherein tumor cells acquire a selective advantage over their normal counterparts and are protected from drug treatment. It is therefore of critical importance to unveil the underlying mechanisms which activate a protumor phenotype of MSCs for defining the unmasked vulnerabilities of hematological cancer cells which could be pharmacologically exploited to disrupt tumor/MSC coupling. The present review focuses on the current knowledge about MSC dysfunction mechanisms in the BMME of hematological cancers, sustaining tumor growth, immune escape, and cancer progression.

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Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia

Cited by 6 publications

References 52 publications

LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

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