M-CSF from Cancer Cells Induces Fatty Acid Synthase and PPARβ/δ Activation in Tumor Myeloid Cells, Leading to Tumor Progression

Park, Jonghanne; Lee, Sang Eun; Hur, Jin; Hong, Eun Byeol; Choi, Jae Il; Yang, Ji Min; Kim, Ju Young; Kim, Young Chan; Cho, Hyun Jai; Peters, Jeffrey M.; Ryoo, Seung Bum; Kim, Young Tae; Kim, Hyo Soo

doi:10.1016/j.celrep.2015.02.024

Cited by 75 publications

(67 citation statements)

References 59 publications

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“…PPARγ activation in macrophages stimulates lung cancer metastasis, while PPARδ activation promotes apoptotic cell clearance . PPARδ activation in myeloid cells promotes tumor invasion through the activation of interleukin 10 . Also, dysregulated lipid metabolism and accumulation of fatty acids in nonalcoholic fatty liver disease patients lead to increased oxidative damage, the loss of CD4 + T helper cells, and impaired antitumor immunity in liver cancer .…”

Section: Discussionmentioning

confidence: 99%

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Lai

2019

Annals of the New York Academy of Sciences

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Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases, including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet little is known about the interactions between genetic and transcriptional events of pathway genes in a pan‐cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 genes demonstrating mutually exclusive patterns of loss‐ and gain‐of‐function phenotypes. These genes successfully predicted patient survival rates in bladder, renal, glioma, liver, and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically relevant relationships between PPARs and hypoxia were observed, where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity, and hypoxia.

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Section: Discussionmentioning

confidence: 99%

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Lai

2019

Annals of the New York Academy of Sciences

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“…In Lewis lung carcinoma, alveolar macrophages and infiltrating TAMs showed distinct lipid profiles with the former expressing COX1 (not COX2), 5‐lipoxygenase and leukotreines, while the latter expressing COX2 and prostaglandins . Moreover, expression of fatty acid synthase in TAMs in the above tumor model, polarized them to a IL‐10‐expressing, pro‐tumor phenotype . E‐FABP‐expressing TAMs have been shown to produce high levels of IFNβ through upregulation of lipid droplet formation .…”

Section: Metabolic Control Of Macrophages In Cancermentioning

confidence: 97%

“…121 Moreover, expression of fatty acid synthase in TAMs in the above tumor model, polarized them to a IL-10-expressing, protumor phenotype. 122 E-FABP-expressing TAMs have been shown to produce high levels of IFNβ through upregulation of lipid droplet formation. 123 Such observations indicate differential lipid metabolism in TAMs which could regulate their pro-or anti-tumor functions.…”

Section: Metabolic Control Of Macrophages In Cancermentioning

confidence: 99%

Metabolic regulation of macrophage phenotype and function

Saha

Shalova

Biswas

2017

Immunological Reviews

194

127

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Studies in the last 20 years have given us a remarkable insight into the functional and phenotypic diversity of macrophages which reflects their integral role in host defence, homeostasis and pathogenesis. Mouse genetics, transcriptomic and epigenetic studies have provided an ontogenic and molecular perspective to the phenotypic diversity of these cells. Recently, metabolic studies have revealed the crucial role of metabolism and metabolites in shaping the phenotype and function of macrophages. Evidence pertaining to this aspect will be reviewed here.

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“…FASN is frequently overexpressed in a variety of tumor types including leukemias (Pizer et al, 1998;Visca et al, 2004;Bandyopadhyay et al, 2005;Alo et al, 1996;Shurbaji et al, 1996;Rashid et al, 1997;Diaz-Blanco et al, 2007) while its expression in healthy adult tissues is low (Weiss et al, 1986), with the exception of the cycling endometrium (Pizer et al, 1997) and lactating breast (Maningat et al, 2009). Interestingly, FASN is upregulated in tumor associated myeloid cells where it activates nuclear receptor peroxisome-proliferatoractivated receptor beta/delta (PPAR/) (Park et al, 2015), a key metabolic transcription factor in tumorigenesis (Peters & Gonzalez, 2009;Zuo et al, 2009). Of note, activation of PPAR/ regulates anti-inflammatory phenotypes of myeloid cells in other biological contexts such as atherosclerosis and obesity (Han Jung-Kyu et al, 2008;Kang et al, 2008;Lee et al, 2003;Odegaard et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

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Switzerland 2 TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138 Abstract Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes.Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34 + hematopoietic progenitors in two AML cohorts (n=68, n=203) (p<0.05). Accordingly, FASN levels decreased during ATRA-mediated granulocytic differentiation of APL cells, partially via autophagic degradation. Furthermore, our data suggests that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG), accelerates the differentiation of APL cell lines and significantly resensitized ATRA refractory non-APL AML cells. Decreasing FASN expression reduced mTOR activity and promoted translocation of transcription factor EB (TFEB) to the nucleus. Lysosomal biogenesis was activated, consistent with TFEB transcriptional activation of CLEAR network genes.Together, our data demonstrates that inhibiting FASN expression in combination with ATRA treatment promotes granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells. BioRXiv

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M-CSF from Cancer Cells Induces Fatty Acid Synthase and PPARβ/δ Activation in Tumor Myeloid Cells, Leading to Tumor Progression

Cited by 75 publications

References 59 publications

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Metabolic regulation of macrophage phenotype and function

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

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