A heterologous expression platform for the discovery of fungal natural products

Content introduction:

  • Hex: A heterologous expression platform for the discovery of fungal natural products
  • Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current
  • Inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
  • The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy
  • Cell–induced CSF1 promotes melanoma resistance to PD1 blockade

1. Hex: A heterologous expression platform for the discovery of fungal natural products

For decades, fungi have been a source of U.S. Food and Drug Administration–approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, Colin J. B. Harvey at Stanford University School of Medicine in Palo Alto, CA, USA and his colleagues developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae. They applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products.

Read more, please click http://advances.sciencemag.org/content/4/4/eaar5459

2. Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current

The assertion that large-diameter nerve fibers have low thresholds and small-diameter fibers have high thresholds in response to electrical stimulation has been held in a nearly axiomatic regard in the field of neuromodulation and neuroprosthetics. In contrast to the short pulses used to evoke action potentials, long-duration ionic direct current has been shown to block neural activity. Fei Yang at Johns Hopkins University in Baltimore, MD, USA and his colleagues propose that the main determinant of the neural sensitivity to direct current block is not the size of the axon but the types of voltage-gated sodium channels prevalent in its neural membrane. On the basis of the variants of voltage-gated sodium channels expressed in different types of neurons in the peripheral nerves, they hypothesized that the small-diameter nociceptive fibers could be preferentially blocked. They show the results of a computational model and in vivo neurophysiology experiments that offer experimental validation of this novel phenomenon.

Read more, please click http://advances.sciencemag.org/content/4/4/eaaq1438

3. Inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. Luis A. Carvajal at Albert Einstein College of Medicine in Bronx, NY, USA and his colleagues demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Their study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

Read more, please click http://stm.sciencemag.org/content/10/436/eaao3003

4. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy

Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others have proposed that some aspect of surgical tumor resection triggers the outgrowth of otherwise-dormant metastases, leading to the synchronous pattern of relapse. Clinical data cannot distinguish between these hypotheses, and previous experimental approaches have not provided clear answers. Such uncertainty hinders the development and application of therapeutic approaches that could potentially reduce early metastatic relapse. Jordan A. Krall at Whitehead Institute for Biomedical Research in Cambridge, MA, USA and his colleagues describe an experimental model system that definitively links surgery and the subsequent wound-healing response to the outgrowth of tumor cells at distant anatomical sites. Specifically, they find that the systemic inflammatory response induced after surgery promotes the emergence of tumors whose growth was otherwise restricted by a tumor-specific T cell response. Furthermore, they demonstrate that perioperative anti-inflammatory treatment markedly reduces tumor outgrowth in this model, suggesting that similar approaches might substantially reduce early metastatic recurrence in breast cancer patients.

Read more, please click http://stm.sciencemag.org/content/10/436/eaan3464

5.  Cell–induced CSF1 promotes melanoma resistance to PD1 blockade

Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Natalie J. Neubert at University of Lausanne (UNIL) in Epalinges, Switzerland and his colleagues show that CSF1 is expressed in human melanoma, and patients with metastatic melanoma have increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of CD8+ T cells and CD163+ TAMs. Human melanoma cell lines consistently produced CSF1 after exposure to melanoma-specific CD8+ T cells or T cell–derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated CD8+ T cells. Mining of publicly available transcriptomic data sets suggested co-enrichment of CD8+ T cells with CSF1 or various TAM-specific markers in human melanoma, which was associated with nonresponsiveness to programmed cell death protein 1 (PD1) checkpoint blockade in a smaller patient cohort. Combination of anti-PD1 and anti–CSF1 receptor (CSF1R) antibodies induced the regression of BRAFV600E-driven, transplant mouse melanomas, a result that was dependent on the effective elimination of TAMs. Collectively, these data implicate CSF1 induction as a CD8+ T cell–dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in melanomas refractory to immune checkpoint blockade and, possibly, other T cell–based therapies.

Read more, please click http://stm.sciencemag.org/content/10/436/eaan3311

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