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Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt–driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer. Whether the Wnt enhanceosome’ components BCL9/9l can affect intestinal homeostasis and tumorigenesis is still unclear. Using conditional Bcl9/9l KO mice, the authors of this study show that the BCL9/9l complex is required for intestinal stem cells to drive tissue regeneration and that loss of BCL9/9l suppresses Wnt-driven transformation.

The original version of this Article contained an error in the spelling of the author Miryam Müller, which was incorrectly given as Miryam Müeller. This has now been corrected in both the PDF and HTML versions of the Article.

It is now well established that tumours undergo changes in cellular metabolism 1 . As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake 2 , we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose 3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types. Mannose reduces the growth of tumour cells by impairing the metabolism of glucose, and enhances cell death when used in combination with conventional chemotherapy.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC , and oncogenic mutations such as mutant KRAS . Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras . Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in Apc Min/+ mice indicating its potential as a metabolic drug target in CRC. In this study, Vande Voorde et al. investigate the potential of untargeted metabolomics as a stratification tool for colorectal cancer (CRC). They present a comprehensive pipeline to uncover metabolic vulnerabilities in CRC based on its genetic origin. With this approach, they show perturbations in methionine metabolism linked to APC deficiency, and identify adenosylhomocysteinase as an actionable therapeutic target.

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24 Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24 Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras . In contrast to previous reports, Rpl24 Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24 Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24 Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24 Bst mutation has a tumour suppressive effect in mouse models.

Practical large-scale mathematical programming involves more than just the application of an algorithm to minimize or maximize an objective function. Before any optimizing routine can be invoked, considerable effort must be expended to formulate the underlying model and to generate the requisite computational data structures. AMPL is a new language designed to make these steps easier and less error-prone. AMPL closely resembles the symbolic algebraic notation that many modelers use to describe mathematical programs, yet it is regular and formal enough to be processed by a computer system; it is particularly notable for the generality of its syntax and for the variety of its indexing operations. We have implemented an efficient translator that takes as input a linear AMPL model and associated data, and produces output suitable for standard linear programming optimizers. Both the language and the translator admit straightforward extensions to more general mathematical programs that incorporate nonlinear expressions or discrete variables.

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras -mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC. Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.

With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC.Competing Interest StatementO.D.K.M. is a co-founder, shareholder and board member of Faeth Therapeutics Inc.

We present optimization algorithms for the design of complex hierarchical systems, motivated by applications to the design of nanoporous materials. Nanoporous materials have a broad range of engineering applications, including gas storage and filtration, electrical energy storage in batteries and capacitors, and catalysis. The design of such materials involves modeling of the material over many length scales, leading to a hierarchy of mathematical models. Our algorithms are also hierarchical in structure with the goal of exploiting the model hierarchy to obtain solutions more rapidly. We discuss the choice of optimization models, initialization schemes, the hierarchical optimization algorithm, software design, and computational results. [PUBLICATION ABSTRACT]

Although algebraic modeling languages are widely used in linear and nonlinear programming applications, their use for combinatorial or discrete optimization has largely been limited to developing integer linear programming models for solution by branch-and-bound procedures. Yet much of a modeling language's underlying structure for expressing integer programs is equally useful for describing more general combinatorial optimization constructs. Constraint programming solvers offer an alternative approach to solving combinatorial optimization problems, in which natural combinatorial constructs are addressed directly within the solution procedure. Hence the growing popularity of constraint programming motivates a variety of extensions to algebraic modeling languages for the purpose of describing combinatorial problems and conveying them to solvers. We examine some of these language extensions along with the significant changes in solver interface design that they require. In particular, we describe how several useful combinatorial features have been added to the AMPL modeling language and how AMPL's general-purpose solver interface has been adapted accordingly. As an illustration of a solver connection, we provide examples from an AMPL driver for ILOG Solver.