Reprogramming of fatty acid metabolism in cancer.

A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies

PARK2 loss promotes cancer progression via redox-mediated inactivation of PTEN

Cancer and Parkinson disease (PD) derive from distinct alterations in cellular processes, yet there are pathogenic mutations that are unequivocally linked to both diseases. Here we expand on our recent findings that loss of parkin RBR E3 ubiquitin protein ligase (PRKN, best known as PARK2)—which is genetically linked to PD—promotes cancer progression via redox-mediated inactivation of phosphatase and tensin homolog (PTEN) by S-nitrosylation.Institute of Cancer Research, Londo

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation.

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments

Increased tumorigenesis associated with loss of the tumor suppressor gene Cadm1

<p>Abstract</p> <p>Background</p> <p><it>CADM1</it> encodes an immunoglobulin superfamily (IGSF) cell adhesion molecule. Inactivation of <it>CADM1</it>, either by promoter hypermethylation or loss of heterozygosity, has been reported in a wide variety of tumor types, thus it has been postulated as a tumor suppressor gene.</p> <p>Findings</p> <p>We show for the first time that <it>Cadm1</it> homozygous null mice die significantly faster than wildtype controls due to the spontaneous development of tumors at an earlier age and an increased tumor incidence of predominantly lymphomas, but also some solid tumors. Tumorigenesis was accelerated after irradiation of <it>Cadm1</it> mice, with the reduced latency in tumor formation suggesting there are genes that collaborate with loss of <it>Cadm1</it> in tumorigenesis. To identify these co-operating genetic events, we performed a <it>Sleeping Beauty</it> transposon-mediated insertional mutagenesis screen in <it>Cadm1</it> mice, and identified several common insertion sites (CIS) found specifically on a <it>Cadm1</it>-null background (and not wildtype background).</p> <p>Conclusion</p> <p>We confirm that <it>Cadm1</it> is indeed a bona fide tumor suppressor gene and provide new insights into genetic partners that co-operate in tumorigenesis when <it>Cadm1</it>-expression is lost.</p

Molecular Pathological Classification of Colorectal Cancer

Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite instability. This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer. Two molecular pathological classification systems for CRC have recently been proposed. Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies. This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups: almost all hypermutated MSI cancers fell into the first category CMS1 (MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Although further research is required to validate these two systems, they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions, particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys[superscript 358]. This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys[superscript 358] to Ser[superscript 358] oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.National Institutes of Health (U.S.) (R03MH085679)National Institutes of Health (U.S.) (1P30CA147882)Burroughs Wellcome FundDamon Runyon Cancer Research FoundationSmith Family FoundationStarr Cancer Consortiu

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression

Asparagine bioavailability governs metastasis in a model of breast cancer.

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression