Nonnative Phragmites australis invasion into Utah wetlands

Phragmites australis (Cav.) Trin. ex Steud. (common reed), already one of the world’s most widespread plant species, has realized rapid range expansion in coastal wetlands of North America in the past century, but little is known about P. australis range expansion in inland wetland systems. We used genetic analyses, aerial photographs, field surveys, and a greenhouse experiment to study the extent and mechanism of nonnative P. australis invasion of Utah wetlands. We collected and genetically analyzed 39 herbarium samples across the state and 225 present-day samples from northern Utah’s major wetland complexes. All samples collected before 1993 and all samples collected outside the major wetlands of northern Utah, including some as recent as 2001, were identified as native (haplotypes A, B, D, and H). Only 10 (4%) of the present-day samples were native, each from small, discrete, low-density stands; the remaining samples were nonnative (haplotype M). Our earliest nonnative sample was collected near the Great Salt Lake in 1993. Around the Great Salt Lake, which contains 40% of Utah’s wetlands, P. australis cover has increased from 20% to 56% over the past 27 years—an increase that appears attributable to the nonnative strain. In a 3-month-long greenhouse experiment, the nonnative haplotype grew taller, had more aboveground biomass, and had a greater above- to belowground biomass ratio than the native haplotypes regardless of nitrogen, phosphorus, or water availability. Nonnative P. australis is rapidly invading the wetlands of northern Utah. Areas in Utah where the native P. australis remains should be identified and protected. Phragmites australis (Cav.) Trin ex Steud (carrizo), una de las especies de plantas más ampliamente distribuida en el mundo, se ha extendido rápidamente en los humedales costeros de Norteamérica en el último siglo, pero se conoce poco sobre la expansión de P. australis en sistemas de humedales del interior. Utilizamos análisis genéticos, fotografías aéreas, estudios de campo y un experimento en invernadero para examinar el alcance y el mecanismo de la invasión de la variedad no nativa de P. australis en los humedales de Utah. Recolectamos 39 muestras de herbario a lo largo del estado y 225 muestras actuales de los mayores complejos de humedales en el norte de Utah, y las sometimos a un análisis genético. Todas las muestras recolectadas antes de 1993 y las que se recolectaron fuera de los mayores humedales del norte de Utah, siendo las más recientes del 2001, fueron identificadas como nativas (haplotipos A, B, D y H). Solo 10 (4%) de las muestras actuales fueron nativas, todas de pequeños carrizales separados con baja densidad; las restantes fueron nonativas (haplotipo M). Nuestra muestra no nativa más antigua se recolectó cerca del Gran Lago Salado en 1993. Alrededor del Gran Lago Salado, el cual contiene el 40% de los humedales del estado de Utah, la cubierta de P. australis incrementó del 20% al 56% durante los últimos 27 años, un aumento que parece atribuirse a la variedad no nativa. En un experimento de invernadero de tres meses, el haplotipo no naivo creció más alto, tenía más biomasa sobre el nivel de la tierra y una mayor proporción de biomasa sobre el nivel de la tierra por biomasa subterránea que los haplotipos nativos sin importar la disponibilidad de nitrógeno, fósforo o agua. El haplotipo no nativo de P. australis está invadiendo rápidamente los humedales del norte de Utah. Las áreas en Utah en donde las variedades nativas permanecen deben ser identificadas y protegidas durante el manejo de carrizos.     

The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

DCC constrains tumour progression via its dependence receptor activity

The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.     

Antibiotics in early life alter the murine colonic microbiome and adiposity

Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.