p53 governs an AT1 differentiation programme in lung cancer suppression.

Lung cancer is the leading cause of cancer deaths worldwide1. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1-4, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.

Multifaceted role for p53 in pancreatic cancer suppression.

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRASG12D-driven PDAC models, we find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p5353,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p5353,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53-null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.

Yellowtail damselfish Chrysiptera parasema can associate predation risk with the acoustic call of a heterospecific damselfish following pairing with conspecific alarm cues.

The ability to detect and respond to the presence of predation risk is under intense selection, especially for small-bodied fishes. Damselfishes (Pomacentridae) use auditory vocalizations during inter- and intrasexual interactions, but it is not known if they can use vocalizations in the context of predator-prey interactions. Here, we test if yellowtail damselfish, Chrysiptera parasema, can learn to associate the territorial vocalization of heterospecific humbug damselfish Dascyllus aruanus with predation risk. In conditioning trials yellowtail damselfish were presented with the territorial call of humbug damselfish while either blank water (control treatment) or chemical alarm cue derived from damaged skin of conspecific yellowtail damselfish was introduced. In conditioning trials, fish exposed to alarm cue exhibited increased activity and spent more time in the water column relative to fish that received the control treatment. After a single conditioning trial, conditioned fish were exposed again to the territorial call of humbug damselfish. Fish conditioned with the call + alarm cue showed increased activity and spent more time in the water column relative to fish that had been conditioned with the control treatment. These data indicate associative learning of an auditory stimulus with predation risk in a species that regularly uses auditory signalling in other contexts. Recordings of conditioning and test trials failed to detect any acoustic calls produced by test fish in response to the perception of predation risk. Thus, although yellowtail damselfish can associate risk with auditory stimuli, we found no evidence that they produce an alarm call.

Post-Operative Spinal Epidural Hematoma: Are We Discontinuing Aspirin Early Enough?

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: (1) To compare the risk of Spinal Epidural Hematoma (SEH) associated with specific pre-operative and post-operative anticoagulation (AC) and antiplatelet medications (APM). (2) To define the incidence of SEH and identify risk factors for SEH in our population. METHODS: Thoracolumbar surgeries between October 2009 and March 2020 were collected. Patients who underwent incision and drainage of a symptomatic SEH were identified. AC and APM was recorded 14 days pre-operatively and post-operatively. Demographics and intra-operative factors were recorded. Relative risk with 95% confidence interval was used, with Bonferroni-corrected P-values <.05 used for significance. RESULTS: 9307 surgeries were identified. 177 (1.9%) patients returned to the OR within 30 days, 37 of whom (.39%) returned due to SEH. Seven patients were on either AC or APM pre-op, and sixteen post-op. Five were on aspirin pre-operatively (RR 3.2, 95% CI 1.25-8.22, P = .015). Risk was not increased in patients on multiple agents. No AC or APM demonstrated increased risk of hematoma post-operatively, despite trends toward significance with multiple agents. The use of a drain and complicated hypertension were associated with increased risk of SEH. CONCLUSIONS: Pre-operative aspirin is associated with increased risk of SEH, even when appropriately discontinued. Appropriately dosed post-operative anticoagulation does not increase the risk of SEH, though being on multiple agents trends toward statistical significance and should be better studied. Surgeons should be vigilant and carefully monitor patients on pre-operative antiplatelet medications for spinal epidural hematoma.

Acquired predator recognition via epidermal alarm cues but not dietary alarm cues by isolated pupfish.

We tested whether Shoshone pupfish Cyprinodon nevadensis shoshone and Amargosa River pupfish C. n. amargosae respond behaviourally to conspecific chemical alarm cues released when epidermal tissue is damaged by a predator. We found that both subspecies reduced activity and vertical position in the water column in response to alarm cues. We then tested if pupfish can use alarm cue to acquire recognition of a novel predator. We trained pupfish with (1) water + odour of largemouth bass fed a diet of earthworms, (2) alarm cues from skin extract (epidermal alarm cues) + odour of bass fed a diet of earthworms, or (3) water + odour of bass fed a diet of pupfish (dietary alarm cues). Pupfish responded to epidermal alarm cues but not to dietary alarm cues. Pupfish were retested with the odour of bass that were fed an earthworm diet. Pupfish that had previously received epidermal alarm cues reduced vertical position and activity relative to the other two treatments. This is the first demonstration of acquired recognition of a novel predator by a pupfish, the first report of partial predator naiveté, and opens the possibility of predator-recognition training as a tool for management and conservation of endangered desert fishes.

Morphological volatility precedes ecological innovation in early echinoderms.

Origins of higher taxonomic groups entail dramatic and nearly simultaneous changes in morphology and ecological function, limiting our ability to disentangle the drivers of evolutionary diversification. Here we phylogenetically compare the anatomy and life habits of Cambrian-Ordovician echinoderms to test which facet better facilitates future success. Rates of morphological evolution are faster and involve more volatile trait changes, allowing morphological disparity to accrue faster and earlier in the Cambrian. However, persistent life-habit evolution throughout the early Palaeozoic, combined with iterative functional convergence within adaptive strategies, results in major expansion of ecospace and functional diversity. The interactions between tempo, divergence and convergence demonstrate not only that anatomical novelty precedes ecological success, but also that ecological innovation is constrained, even during a phylum's origin.

Cell of Origin Influences Pancreatic Cancer Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell-derived and acinar cell-derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. SIGNIFICANCE: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.This article is highlighted in the In This Issue feature, p. 521.