Topics overview: Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival, How oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells, Scientist uncover a new inducer of mammalian heart regeneration, highlighting fundamental roles of the ECM in cardiac repair, Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and Structure of the human multidrug transporter ABCG2.
1. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here Sushrut Kamerkar at University of Texas MD Anderson Cancer Center in Texas, USA and his colleagues show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Their results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.
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2. Nutrient acquisition strategies of mammalian cells
Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane transporters and endolysosomal pathways. By using different nutrient sources, cells gain metabolic flexibility to survive periods of starvation. Quiescent cells take up sufficient nutrients to sustain homeostasis. However, proliferating cells depend on growth-factor-induced increases in nutrient uptake to support biomass formation. Here, Wilhelm Palm at Memorial Sloan Kettering Cancer Center in New York, USA and his colleagues review cellular nutrient acquisition strategies and their regulation by growth factors and cell-intrinsic nutrient sensors. They also discuss how oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells.
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3. The extracellular matrix protein Agrin promotes heart regeneration in mice
The adult mammalian heart is non-regenerative due to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only for the first week of life. Here Elad Bassat at Weizmann Institute of Science in Rehovot, Israel and his colleagues show that changes in the composition of the extracellular matrix (ECM) during this week can affect cardiomyocyte growth and differentiation in mice. They identify Agrin, a component of neonatal ECM, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant Agrin promotes the division of mouse and human iPSC-derived cardiomyocytes via a mechanism that involves the disassembly of the dystrophin glycoprotein complex and Yap and ERK-mediated signaling. In vivo, a single administration of Agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests additional therapeutic mechanisms. Collectively, they uncover a new inducer of mammalian heart regeneration, highlighting fundamental roles of the ECM in cardiac repair.
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4. A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis
Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here Ujjini H. Manjunatha at Novartis Institute for Tropical Diseases in Chromos, Singapore and his colleagues establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, they identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Their results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis.
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5. Structure of the human multidrug transporter ABCG2
ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here Nicholas M. I. Taylor at University of Basel in Basel, Switzerland and his colleagues present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. They visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. They observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, their results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
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