Abstract
Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic ...activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.
Allopatric speciation may be the principal mechanism generating new species. Yet, it remains difficult to judge the generality of this process because few studies have provided evidence that ...geographic isolation has triggered the development of reproductive isolation over multiple species of a regional fauna. Here, we first combine results from new empirical data sets (7 taxa) and published literature (9 taxa) to show that the eastern Great Lakes drainage represents a multispecies suture zone for glacial lineages of freshwater fishes with variable levels of genetic divergence. Second, we performed amplified fragment length polymorphism analyses among four pairs of lineages. Results indicate that lineages with relatively deep levels of mtDNA 5′ COI (barcode) sequence divergence (>2%) developed strong reproductive barriers, while lineages with lower levels of divergence show weaker reproductive isolation when found in sympatry. This suggests that a threshold of 2% sequence divergence at mtDNA could be used as a first step to flag cryptic species in North American freshwater fishes. By describing different levels of divergence and reproductive isolation in different co‐occurring fishes, we offer strong evidence that allopatric speciation has contributed significantly to the diversification of north‐eastern American freshwater fishes and confirm that Pleistocene glacial cycles can be viewed as a ‘speciation pump’ that played a predominant role in generating biodiversity.
•Genome stability is intimately linked to speciation and evolution.•Genome stability is a complex trait.•Genome instability may be a widespread cause of hybrid incompatibility.•Hybridization can ...trigger genome instability in multiple ways.
Genome stability ensures individual fitness and reliable transmission of genetic information. Hybridization between diverging lineages can trigger genome instability, highlighting its potential role in post-zygotic reproductive isolation. We argue that genome instability is not merely one of several types of hybrid incompatibility, but rather that genome stability is one of the very first and most fundamental traits that can break down when two diverged genomes are combined. Future work will reveal how frequent and predictable genome instability is in hybrids, how it affects hybrid fitness, and whether it is a direct cause or consequence of speciation.
Identifying the molecular basis of reproductive isolation among diverging lineages represents an essential step toward understanding speciation in natural populations. Postzygotic barriers can lead ...to hybrid breakdown, a syndrome that has been documented in several systems, potentially involving the reactivation of transposable elements. In northeastern North America, two lake whitefish lineages have repeatedly colonized postglacial lakes ∼12,000 years ago, and a dwarf limnetic species has evolved multiple times from the normal benthic species. Reproductive isolation is incomplete between them; viable hybrids can be generated in the laboratory but significant mortality occurs and is associated with a malformed phenotype in backcross embryos, thus revealing a hybrid breakdown syndrome. By means of RNA-seq analyses, the objective of this study was to determine which genes were misregulated in hybrids and rigorously test the hypothesis of transposable element reactivation. We compared the transcriptomic landscape in pure embryos, F1-hybrids, and healthy and malformed backcrosses at the late embryonic stage. Extensive expression differences consistent with previously documented adaptive divergence between pure normal and dwarf embryos were identified for the first time. Pronounced transcriptome-wide deregulation in malformed backcrosses was observed, with over 15% of transcripts differentially expressed in all comparisons, compared with 1.5% between pure parental forms. Convincing evidence of transposable elements and noncoding transcripts reactivation in malformed backcrosses is presented. We propose that hybrid breakdown likely results from extensive genomic incompatibilities, plausibly encompassing transposable elements. Combined with previous studies, these results reveal synergy among many reproductive barriers, thus maintaining divergence between these two young whitefish species.
Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. PALB2's tumor-suppressing effect is thought to be based on its ability to facilitate BRCA2's ...function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to stimulate strand invasion, a vital step of homologous recombination. This stimulation occurs through reinforcing biochemical mechanisms, as PALB2 alleviates inhibition by RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Our studies provide the first biochemical insights into PALB2's function with piBRCA2 as a mediator of homologous recombination in DNA double-strand break repair.
Drosophila telomeres have been maintained by three families of active transposable elements (TEs), HeT-A, TAHRE, and TART, collectively referred to as HTTs, for tens of millions of years, which ...contrasts with an unusually high degree of HTT interspecific variation. While the impacts of conflict and domestication are often invoked to explain HTT variation, the telomeres are unstable structures such that neutral mutational processes and evolutionary tradeoffs may also drive HTT evolution. We leveraged population genomic data to analyze nearly 10,000 HTT insertions in 85 Drosophila melanogaster genomes and compared their variation to other more typical TE families. We observe that occasional large-scale copy number expansions of both HTTs and other TE families occur, highlighting that the HTTs are, like their feral cousins, typically repressed but primed to take over given the opportunity. However, large expansions of HTTs are not caused by the runaway activity of any particular HTT subfamilies or even associated with telomere-specific TE activity, as might be expected if HTTs are in strong genetic conflict with their hosts. Rather than conflict, we instead suggest that distinctive aspects of HTT copy number variation and sequence diversity largely reflect telomere instability, with HTT insertions being lost at much higher rates than other TEs elsewhere in the genome. We extend previous observations that telomere deletions occur at a high rate, and surprisingly discover that more than one-third do not appear to have been healed with an HTT insertion. We also report that some HTT families may be preferentially activated by the erosion of whole telomeres, implying the existence of HTT-specific host control mechanisms. We further suggest that the persistent telomere localization of HTTs may reflect a highly successful evolutionary strategy that trades away a stable insertion site in order to have reduced impact on the host genome. We propose that HTT evolution is driven by multiple processes, with niche specialization and telomere instability being previously underappreciated and likely predominant.
Background
Pelvic vein thrombosis (PVT) is a rare complication of pregnancy that can lead to life‐threatening complications, such as pulmonary embolism (PE).
Objective
To describe characteristics of ...PVT and its treatment in pregnancy in the province of Quebec, Canada.
Patients/Methods
We developed a province‐wide case series of PVT in pregnancy including four tertiary care centers and the Registry of Rare Diseases of the Groupe d’Étude en Médecine Obstétricale du Québec. Using diagnostic codes, we included cases with confirmed PVT on imaging during pregnancy or within 6 weeks postpartum from July 2003 to June 2018.
Results
A total of 47 cases were identified. PVT diagnosis was generally made in the early postpartum period (median of 9 interquartile range (IQR) 4.5–12 days postpartum). Most PVT (94%) included in this series were symptomatic. Women presented primarily with abdominal pain (77%) and fever (55%), often prolonged despite antibiotics (mean 4.45 ± 2.39 days, with 39% having fever for more than 5 days). The most common risk factor was surgery (57%) and peripartum infections (54%). Thirty‐eight (83%) women received antibiotics and 41 (89%) were anticoagulated. Three cases of PE (7%) occurred concomitantly, 11% of women required intensive care, and 19% had inferior vena cava (IVC) clot extension. The episode resulted in prolonged hospitalization (median 6 IQR 3–10.75 days), with 48% being hospitalized more than 7 days.
Conclusion
Symptomatic PVT has significant clinical implications with prolonged fever and risks of extension in the IVC and PE, leading to prolonged hospitalization including in the intensive care unit. Therapeutic anticoagulation and antibiotics, when infection is documented, should be considered for management.
In some eukaryotes, germline and somatic genomes differ dramatically in their composition. Here we characterise a major germline-soma dissimilarity caused by a germline-restricted chromosome (GRC) in ...songbirds. We show that the zebra finch GRC contains >115 genes paralogous to single-copy genes on 18 autosomes and the Z chromosome, and is enriched in genes involved in female gonad development. Many genes are likely functional, evidenced by expression in testes and ovaries at the RNA and protein level. Using comparative genomics, we show that genes have been added to the GRC over millions of years of evolution, with embryonic development genes bicc1 and trim71 dating to the ancestor of songbirds and dozens of other genes added very recently. The somatic elimination of this evolutionarily dynamic chromosome in songbirds implies a unique mechanism to minimise genetic conflict between germline and soma, relevant to antagonistic pleiotropy, an evolutionary process underlying ageing and sexual traits.
AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. In the current study, we report AXL expression in HER2-positive (HER2+) breast cancers where it correlates ...with poor patient survival. Using murine models of HER2+ breast cancer, Axl, but not its ligand Gas6, was found to be essential for metastasis. We determined that AXL is required for intravasation, extravasation, and growth at the metastatic site. We found that AXL is expressed in HER2+ cancers displaying epithelial-to-mesenchymal transition (EMT) signatures where it contributes to sustain EMT. Interfering with AXL in a patient-derived xenograft (PDX) impaired transforming growth factor β (TGF-β)-induced cell invasion. Last, pharmacological inhibition of AXL specifically decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential anti-metastatic co-therapeutic target for the treatment of HER2+ breast cancers.
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•AXL expression correlates with poor outcome of HER2+ breast cancer patients•Co-signaling of HER2 and AXL mediates metastasis of HER2+ breast cancer•AXL promotes the mesenchymal phenotypes of HER2+ cancer cells for metastasis•Pharmacological inhibition of AXL reduces metastasis in HER2+ breast cancer mice
Metastasis is responsible for the majority of breast cancer deaths. Goyette et al. report that AXL is expressed in HER2+ human tumors that acquire aggressive features. Blockade of AXL in mice decreases metastasis. These results suggest that co-targeting AXL and HER2 may limit the metastatic progression of HER2+ breast cancer.
We present Hypertension Canada’s inaugural evidence-based Canadian recommendations for the management of hypertension in pregnancy. Hypertension in pregnancy is common, affecting approximately 7% of ...pregnancies in Canada, and requires effective management to reduce maternal, fetal, and newborn complications. Because of this importance, these guidelines were developed in partnership with the Society of Obstetricians and Gynaecologists of Canada with the main common objective of improving the management of women with hypertension in pregnancy. Guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children are published separately. In this first Hypertension Canada guidelines for hypertension in pregnancy, 7 recommendations for the management of nonsevere and severe hypertension in pregnancy are presented. For nonsevere hypertension in pregnancy (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 80-109 mm Hg), we provide guidance for the threshold for initiation of antihypertensive therapy, blood pressure targets, as well as first- and second-line antihypertensive medications. Severe hypertension (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) requires urgent antihypertensive therapy to reduce maternal, fetal, and newborn adverse outcomes. The specific evidence and rationale underlying each of these guidelines are discussed.
Nous présentons les premières recommandations d'Hypertension Canada fondées sur des données probantes pour la prise en charge de l'hypertension pendant la grossesse. L'hypertension en cours de grossesse, un trouble fréquent qui touche 7 % des grossesses au Canada, nécessite une prise en charge efficace pour réduire les complications tant chez la mère que chez le fœtus et le nouveau-né. Compte tenu de leur importance, ces lignes directrices ont été élaborées en partenariat avec la Société des obstétriciens et gynécologues du Canada avec l'objectif principal commun d'améliorer la prise en charge des femmes hypertendues pendant leur grossesse. Les lignes directrices relatives au diagnostic, à l'évaluation, à la prévention et au traitement de l'hypertension chez l'adulte et l'enfant sont publiées séparément. Dans ces premières lignes directrices sur l'hypertension pendant la grossesse d'Hypertension Canada, sept recommandations pour la prise en charge de l'hypertension bénigne et grave chez les femmes enceintes sont présentées. Pour l'hypertension bénigne pendant la grossesse (pression artérielle systolique de 140 à 159 mm Hg et/ou pression artérielle diastolique de 80 à 109 mm Hg), nous donnons des indications relatives au seuil d'instauration du traitement antihypertenseur, aux pressions artérielles cibles et aux médicaments antihypertenseurs de première et de deuxième intention. L'hypertension grave (pression artérielle systolique ≥ 160 mm Hg et/ou pression artérielle diastolique ≥ 110 mm Hg) nécessite un traitement antihypertenseur urgent pour réduire ses effets néfastes chez la mère, le fœtus et le nouveau-né. Les données probantes et la justification qui sous-tendent chacune de ces lignes directrices sont analysées.
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