Activation of Farnesoid X Receptor impairs the tumor-promoting function of breast cancer-associated fibroblasts

Barone, Ines; Vircillo, Valentina; Giordano, Cinzia; Gelsomino, Luca; Győrffy, Balázs; Tarallo, Roberta; Rinaldi, Antonio; Bruno, Giuseppina; Caruso, A.; Romeo, Francesco; Bonofiglio, Daniela; Andò, Sebastiano; Catalano, Stefania

doi:10.1016/j.canlet.2018.08.026

Cited by 29 publications

(25 citation statements)

References 57 publications

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“…Other studies have shown FXR protein expression in these cell lines and tumors using Western blot analysis and IHC (27,(44)(45)(46). As a general finding, FXR signaling in these cell lines led to oncosuppressive effects (27,44,45). Consistent with these observations, high FXR expression in human breast tumors was associated with favorable patient survival in one analysis (46).…”

Section: Discussionsupporting

confidence: 60%

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Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Tang

Putluri

Ambati

et al. 2019

Clinical Cancer Research

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Purpose: Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology. Experimental Design: We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments. Results: LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G 2-M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors. Conclusions: We describe the unexpected accumulation of liver-and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.

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Section: Discussionsupporting

confidence: 60%

“…S8). Other studies have shown FXR protein expression in these cell lines and tumors using Western blot analysis and IHC (27,(44)(45)(46). As a general finding, FXR signaling in these cell lines led to oncosuppressive effects (27,44,45).…”

Section: Discussionmentioning

confidence: 68%

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Tang

Putluri

Ambati

et al. 2019

Clinical Cancer Research

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“…188,189 High FXR associated with smaller tumor size, high proliferation rate, relapse-free survival, distant metastasis-free survival, and overall survival in BC patients. 190,191 Indeed, FXR is an independent prognostic factor for overall and disease-free patients' survival. 191 Potential mechanisms of action include FXR-mediated inhibition of leptin-induced oncogenic cancer-associated fibroblasts (CAFs) in multiple BC cell lines by increasing suppressor of the cytokine signaling 3 (SOCS3) expression downstream of FXR-implicating an obesity-specific susceptibility.…”

Section: Can Bas Also Influence Bc? the Presence Of Bas In Breast Tissuementioning

confidence: 99%

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Sipe

Chaib

Pingili

et al. 2020

Immunological Reviews

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Bile acids (BAs) are known facilitators of nutrient absorption but recent paradigm shifts now recognize BAs as signaling molecules regulating both innate and adaptive immunity. Bile acids are synthesized from cholesterol in the liver with subsequent microbial modification and fermentation adding complexity to pool composition. Bile acids act on several receptors such as Farnesoid X Receptor and the G proteincoupled BA receptor 1 (TGR5). Interestingly, BA receptors (BARs) are expressed on immune cells and activation either by BAs or BAR agonists modulates innate and adaptive immune cell populations skewing their polarization toward a more tolerogenic anti-inflammatory phenotype. Intriguingly, recent evidence also suggests that BAs promote anti-tumor immune response through activation and recruitment of tumoricidal immune cells such as natural killer T cells. These exciting findings have redefined BA signaling in health and disease wherein they may suppress inflammation on the one hand, yet promote anti-tumor immunity on the other hand. In this review, we provide our readers with the most recent understanding of the interaction of BAs with the host microbiome, their effect on innate and adaptive immunity in health and disease with a special focus on obesity, bariatric surgery-induced weight loss, and immune checkpoint blockade in cancer. K E Y W O R D S bariatric surgery, immunometabolism, microbiome, mitochondria, obesity, tumor microenvironment | 221 SIPE Et al.

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“…Since the expression levels of FXR in implanted EGI1 cells were negligible, whereas In addition, since FXR expression has been identified in hepatic stellate cells, one of the precursors of CAFs, 187 other possibility is that the inhibitory action of obeticolic acid could be mediated by a direct action on these stromal cells, as it has been described in breast cancer. 188 Thus, further preclinical investigations are still needed to support a beneficial effect of obeticholic acid treatment on CCA outcome.…”

Section: Fxr-and Tgr5-mediated Pathwaysmentioning

confidence: 99%

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Fouassier

Marzioni

Afonso

et al. 2019

Liver International

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Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell‐intrinsic alterations at the genetic and epigenetic level but also pro‐tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale‐based and genotype‐matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.

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Activation of Farnesoid X Receptor impairs the tumor-promoting function of breast cancer-associated fibroblasts

Cited by 29 publications

References 57 publications

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

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