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Objectives: Indications of mitochondrial dysfunction are commonly seen in liver diseases, but data are scarce in primary sclerosing cholangitis (PSC). Analyzing circulating and liver-resident molecules indirectly reflecting mitochondrial dysfunction, we aimed to comprehensively characterize this deficit in PSC, and whether this was PSC specific or associated with cholestasis. Materials and methods: We retrospectively included plasma from 191 non-transplant patients with large-duct PSC and 100 healthy controls and explanted liver tissue extracts from 24 PSC patients and 18 non-cholestatic liver disease controls. Using mass spectroscopy, we profiled lipids and fatty acids, carnitine, acylcarnitines, and metabolites in the tryptophan-kynurenine-nicotinamide pathway. Results: Hierarchal clustering of fatty acid levels identified patients with PSC and healthy controls as separate clusters. Compared to healthy controls, PSC patients had increased levels of monounsaturated fatty acids (MUFA) and palmitate (C16:0) in plasma, but reduced levels of long-chain saturated fatty acids (SFAs). These findings were more pronounced in PSC patients with cholestasis. Several n-3 polyunsaturated fatty acids were elevated in PSC but not associated with cholestasis. Acylcarnitine ratios C2/C5 and C2/C3 were elevated while C2/C16 was reduced in PSC, indicating impaired mitochondrial fatty acid oxidation of medium-long chained fatty acids. Levels of intermediates in the tryptophan-kynurenine pathway indicated impaired NAD biosynthesis, suggesting impaired energy supply to mitochondria in PSC. Conclusions: We found that mitochondrial dysfunction was prominent in PSC and associated with increasing cholestasis. Whether this is merely a marker of liver disease and severity, or an underlying driver and potential therapeutic target in PSC remains to be explored. [ABSTRACT FROM AUTHOR] more...

Background/Aims: It was recently reported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to patients diagnosed with non-metastatic PDAC. Method: We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 patients with borderline resectable or locally advanced PDAC, collected before initiating neoadjuvant chemotherapy. The majority (61%) of the patients were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival. Results: The median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203–417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log2(3-IAA) was 0.93, 95% confidence interval (CI) [0.74–1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log2(3-IAA) was 0.87, 95% CI [0.68–1.12], p=0.28. Conclusion: Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC undergoing chemotherapy may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA's predictive value in different categories of PDAC before implementation attempts in human studies are initiated. [ABSTRACT FROM AUTHOR] more...

This corrects the article DOI: 10.1038/bjc.2017.346 [ABSTRACT FROM AUTHOR]

Background/aims: It was recently reported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to patients diagnosed with non-metastatic PDAC., Method: We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 patients with borderline resectable or locally advanced PDAC, collected before initiating neoadjuvant chemotherapy. The majority (61%) of the patients were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival., Results: The median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203-417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log 2 (3-IAA) was 0.93, 95% confidence interval (CI) [0.74-1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log 2 (3-IAA) was 0.87, 95% CI [0.68-1.12], p=0.28., Conclusion: Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC undergoing chemotherapy may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA's predictive value in different categories of PDAC before implementation attempts in human studies are initiated., Competing Interests: Authors AM and PU were employed by the company BEVITAL AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Braadland, Farnes, Kure, Yaqub, McCann, Ueland, Labori and Hov.) more...

Background: People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC., Methods: We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies., Results: We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival., Conclusions: In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.) more...

The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β 2 -adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence. IMPLICATIONS: This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC., (©2019 American Association for Cancer Research.) more...

The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17. more...