bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2020‒12‒27
six papers selected by
Giovanny Rodriguez Blanco
University of Edinburgh

  1. Mol Cell. 2020 Dec 15. pii: S1097-2765(20)30827-3. [Epub ahead of print]
      In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
    Keywords:  MCT2; PHGDH; breast cancer; lung environment; mTORC1; metastasis formation; pyruvate; serine biosynthesis; α-ketoglutarate
  2. Int J Mol Sci. 2020 Dec 17. pii: E9622. [Epub ahead of print]21(24):
      Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.
    Keywords:  glutamine metabolism; ligand; liver X receptor; oxidative stress; pancreatic cancer
  3. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Dec 13. pii: S1388-1981(20)30253-5. [Epub ahead of print]1866(3): 158861
      Fatty acid metabolism and oxidation capacity in the placenta, which likely affects the rate and composition of lipid delivered to the fetus remains poorly understood. Long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), are critical for fetal growth and brain development. We determined the impact of maternal obesity on placental fatty acid oxidation, esterification and transport capacity by measuring PhosphatidylCholine (PC) and LysoPhosphatidylCholine (LPC) containing DHA by mass spectrometry in mother-placenta-baby triads as well as placental free carnitine and acylcarnitine metabolites in women with normal and obese pre-pregnancy BMI. Placental protein expression of enzymes involved in beta-oxidation and esterification pathways, MFSD2a (lysophosphatidylcholine transporter) and OCTN2 (carnitine transporter) expression in syncytiotrophoblast microvillous (MVM) and basal (BM) membranes were determined by Western Blot. Maternal obesity was associated with decreased umbilical cord plasma DHA in LPC and PC fractions in male, but not female, fetuses. Basal membrane MFSD2a protein expression was increased in placenta of males of obese mothers. In female placentas, despite an increased MVM OCTN2 expression, maternal obesity was associated with a reduced MUFA-carnitine levels and increased esterification enzymes. We speculate that lower DHA-PL in fetal circulation of male offspring of obese mothers, despite a significant increase in transporter expression for LPC-DHA, may lead to low DHA needed for brain development contributing to neurological consequences that are more prevalent in male children. Female placentas likely have reduced beta-oxidation capacity and appear to store FA through greater placental esterification, suggesting impaired placenta function and lipid transfer in female placentas of obese mothers.
    Keywords:  Fetus; Human pregnancy; LPC-DHA; MFSD2a; Maternal-fetal exchange; Metabolic disorders
  4. Mol Metab. 2020 Dec 17. pii: S2212-8778(20)30217-9. [Epub ahead of print] 101143
      BACKGROUND: The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide in parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or nonalcoholic fatty liver (NAFL). In a subset of people with NAFL, the disease can progress to nonalcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, yet there are still gaps in our mechanistic understanding of the precise metabolic triggers for disease worsening.SCOPE OF THE REVIEW: The transition from NAFL to NASH likely involves a complex constellation of multiple factors, both intrinsic and extrinsic to the liver. This review will focus on the early metabolic events in the establishment of NAFL and initial stages of NASH. We will discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and will highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis.
    CONCLUSIONS: The close association of NAFL with features of the metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and release of lipotoxic lipids, hepatic de novo lipogenesis (DNL) and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating progression of the disease. Human genetic variants linked to NASH risk to date are heavily biased towards genes involved in regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.
    Keywords:  NAFLD; NASH; adipose tissue; fructose; lipotoxicity; obesity
  5. Nat Commun. 2020 Dec 21. 11(1): 6422
      Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5+ stem cells and human colon carcinomas with increased nuclear β-catenin. High levels of MLL1 are associated with poor survival of colon cancer patients. The genetic ablation of Mll1 in mice prevents Wnt/β-catenin-driven adenoma formation from Lgr5+ intestinal stem cells. Ablation of Mll1 decreases the self-renewal of human colon cancer spheres and halts tumor growth of xenografts. Mll1 controls the expression of stem cell genes including the Wnt/β-catenin target gene Lgr5. Upon the loss of Mll1, histone methylation at the stem cell promoters switches from activating H3K4 tri-methylation to repressive H3K27 tri-methylation, indicating that Mll1 sustains stem cell gene expression by antagonizing gene silencing through polycomb repressive complex 2 (PRC2)-mediated H3K27 tri-methylation. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll1 regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. Our results demonstrate that Mll1 is an essential epigenetic regulator of Wnt/β-catenin-induced intestinal tumorigenesis and cancer stemness.
  6. Cancer Lett. 2020 Dec 16. pii: S0304-3835(20)30679-0. [Epub ahead of print]
      Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.
    Keywords:  ACSL4; Hepatocellular carcinoma; Lipogenesis; SREBP1