Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis

Masri, Selma; Papagiannakopoulos, Thales; Kinouchi, Kenichiro; Liu, Yu; Cervantes, Marlene; Baldi, Pierre; Jacks, Tyler; Sassone–Corsi, Paolo

doi:10.1016/j.cell.2016.04.039

Cited by 202 publications

(217 citation statements)

References 66 publications

(77 reference statements)

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“…PAF-R are mainly expressed by mesenchymal cells, which may explain the implication of adipose, muscle, liver, and heart tissue, as well as gut barrier and brain dysfunctions in cachexia, supporting our proposed model (31,32,(62)(63)(64). Also, the described crosstalk between wasting of fat tissue and skeletal muscle is compatible with the proposed mechanism (65)(66)(67).…”

Section: Discussionsupporting

confidence: 85%

“…Additionally, the targeted metabolomics analysis revealed significant decreased concentrations of several long-chain and highly unsaturated phosphatidylcholines (PC) (Fig. 3), which has been related to dysfunction of lipid synthesis in liver, as well as to altered properties of cell membranes (32,33). Under oxidative conditions, typically developing upon tumor progression, PCs may be converted into platelet activating factor (PAF) and other platelet activating factor receptor (PAF-R) agonists (34,35).…”

Section: Metabolomics Analyses Of Serum Samples Revealed Downregulatimentioning

confidence: 99%

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Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified Serum is the most important diagnostic sample type because of its minimal invasive access, a relatively high stability and its comprehensive representation of the physiological state of an individual. The latest technological development of mass spectrometric instruments, such as high resolution orbitrap instruments, improved substantially the quality and reliability of serum proteomics data (1). Shotgun proteomics analysis using the orbitrap technology is mainly applied for protein screening purposes (2). This method allows performing untargeted analyses, applicable for hypothesis-generating clinical applications. Targeted proteomics using triple-quadrupole mass spectrometric instruments, represents a complementary approach which is applied for protein quantification, hypotheses verification and validation (3). Enormous efforts have been invested in the last decades focusing on serum biomarker discovery (4). However, mass spectrometrybased proteomics analyses hardly managed to cope with biological variation. As a consequence, almost no clinically validated biomarker has emerged from these investigations yet, and a lot of questions about pathophysiological mechanisms remain unanswered.Using mass spectrometry-based proteomics, we have previously investigated melanoma and neighboring stroma cells, focusing on the identification of biomarkers associated with intrinsic and extrinsic drug resistance (5). In the present article, we followed the question how metastatic melanoma may reprogram distant organ functions, and how these...

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Section: Discussionsupporting

confidence: 85%

Section: Metabolomics Analyses Of Serum Samples Revealed Downregulatimentioning

confidence: 99%

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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show abstract

“…Finally, we have not addressed the possibility that the fatty acids that are liberated from adipose tissue and not readily metabolized by reprogrammed livers may be a source of macronutrients to be used by cancer cells for growth (Kamphorst et al., 2013). Nevertheless, the observation of tumor-induced IL-6 reprogramming hepatic ketogenesis, when taken together with the recent report of lung cancer rewiring hepatic circadian homeostasis involving insulin, glucose, and lipid metabolism (Masri et al., 2016), suggests that the liver may be a specific target of tumor-induced effects on the host, presumably for the benefit of the tumor and the detriment of the host.…”

Section: Discussionmentioning

confidence: 98%

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity

et al. 2016

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SummaryIn patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.

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“…Cancer operated as an endogenous reorganizer of circadian metabolism by affecting transcripts and metabolites cycling in the liver, while having no effect on the core clock. Inflammatory signaling, the STAT3-Socs3 pathway, downstream disruption of AKT, and AMPK were shown to mediate cancer rewiring of circadian hepatic metabolism 19 .…”

Section: Circadian Dysrhythmia and Cancermentioning

confidence: 99%