Psychobiotics and the Microbiota-Gut-Brain Axis: Where Do We Go from Here?

The bidirectional relationship between the gut microbiota and the nervous system is known as the microbiota-gut-brain axis (MGBA). The MGBA controls the complex interactions between the brain, the enteric nervous system, the gut-associated immune system, and the enteric neuroendocrine systems, regulating key physiological functions such as the immune response, sleep, emotions and mood, food intake, and intestinal functions. Psychobiotics are considered tools with the potential to modulate the MGBA through preventive, adjunctive, or curative approaches, but their specific mechanisms of action on many aspects of health are yet to be characterized. This narrative review and perspectives article highlights the key paradigms needing attention as the scope of potential probiotics applications in human health increases, with a growing body of evidence supporting their systemic beneficial effects. However, there are many limitations to overcome before establishing the extent to which we can incorporate probiotics in the management of neuropsychiatric disorders. Although this article uses the term probiotics in a general manner, it remains important to study probiotics at the strain level in most cases.

Review and Perspectives on Bifidobacterium lactis for Infants' and Children's Health.

The influence of microbiota dysbiosis in early life is increasingly recognized as a risk factor for the development of several chronic diseases later in life, including an increased risk of asthma, eczema, allergies, obesity, and neurodevelopmental disorders. The question whether the potential lifelong consequences of early life dysbiosis could be mitigated by restoring microbiota composition remains unresolved. However, the current evidence base suggests that protecting the normal development of the microbiome during this critical developmental window could represent a valuable public health strategy to curb the incidence of chronic and lifestyle-related diseases. Probiotic Bifidobacteria are likely candidates for this purpose in newborns and infants considering the natural dominance of this genus on microbiota composition in early life. Moreover, the most frequently reported microbiota composition alteration in association with newborn and infant diseases, including necrotizing enterocolitis and diarrhea, is a reduction in Bifidobacteria levels. Several studies have assessed the effects of B. animalis subsp. lactis strains in newborns and infants, but recent expert opinions recommend analyzing their efficacy at the strain-specific level. Hence, using the B94 strain as an example, this review summarizes the clinical evidence available in infants and children in various indications, discussing the safety and potential modes of actions while providing perspectives on the concept of "non-infant-type" probiotics for infants' health.

Total Transit Time and Probiotic Persistence in Healthy Adults: A Pilot Study.

Background/Aims: Motility, stool characteristics, and microbiota composition are expected to modulate probiotics' passage through the gut but their effects on persistence after intake cessation remain uncharacterized. This pilot, open-label study aims at characterizing probiotic fecal detection parameters (onset, persistence, and duration) and their relationship with whole gut transit time (WGTT). Correlations with fecal microbiota composition are also explored. Methods: Thirty healthy adults (30.4 ± 13.3 years) received a probiotic (30 × 109 CFU/capsule/day, 2 weeks; containing Lactobacillus helveticus R0052, Lacticaseibacillus paracasei HA-108, Bifidobacterium breve HA-129, Bifidobacterium longum R0175, and Streptococcus thermophilus HA-110). Probiotic intake was flanked by 4-week washout periods, with 18 stool collections throughout the study. WGTT was measured using 80% recovery of radio-opaque markers. Results: Tested strains were detected in feces ~1-2 days after first intake and persistence after intake cessation was not significantly different for R0052, HA-108, and HA-129 (~3-6 days). We identified 3 WGTT subgroups within this population (named Fast, Intermediate, and Slow), which could be classified by machine learning with high accuracy based on differentially abundant taxa. On average, R0175 persisted significantly longer in the intermediate WGTT subgroup (~8.5 days), which was mainly due to 6 of the 13 Intermediate participants for whom R0175 persisted ≥ 15 days. Machine learning classified these 13 participants according to their WGTT cluster (≥ 15 days or < 5 days) with high accuracy, highlighting differentially abundant taxa potentially associated with R0175 persistence. Conclusion: These results support the notion that host-specific parameters such as WGTT and microbiota composition should be considered when designing studies involving probiotics, especially for the optimization of washout duration in crossover studies but also for the definition of enrollment criteria or supplementation regimen in specific populations.

Impact of probiotic supplementation on exercise endurance among non-elite athletes: study protocol for a randomized, placebo-controlled, double-blind, clinical trial.

BACKGROUND: Some probiotics appear to improve athletic performance, endurance, and recovery after intense exercise. Other formulations may provide performance-related benefits via immune and gastrointestinal functions in athletic individuals. However, few formulations have been studied for both types of effects among non-elite athletes. The primary objective of this study is to assess the ergogenic effects of a probiotic on high-intensity endurance running performance in non-elite runners. Secondary objectives include assessment of perceived exertion, blood chemistry, immune and stress biomarkers, cold and flu symptoms, and gastrointestinal health after the probiotic intervention. METHODS: This 9-week randomized, placebo-controlled, double-blind, parallel trial will assess the ergogenic effects of a probiotic (5 billion colony-forming units/day, for 6 weeks) in healthy, non-elite runners (N=32; 18-45 years). Participants will be monitored via daily and weekly questionnaires during the 2-week pre-baseline, 6-week intervention, and 1-week washout. Questionnaires will inquire about activity, muscle soreness, gastrointestinal symptoms, cold and flu symptoms, stool form and frequency, and adverse events. During the pre-baseline visit, maximal oxygen uptake (V̇O2 max) is assessed to set appropriate individualized workload settings for the treadmill time-to-exhaustion endurance tests. These time-to-exhaustion endurance running tests will be completed at an intensity of 85% VO2max at baseline and final visits. During these tests, self-perceived exercise effort will be rated via the Borg Rating of Perceived Exertion scale and finger sticks assessing capillary blood glucose and lactate concentrations will be collected every 3 min. Additional questionnaires will assess diet and motivation to exercise. Body composition will be assessed using air displacement plethysmography at the baseline and final visits. Hypotheses will be tested using two-sided tests, and a linear model and with a type I error rate of α=0.05. Primary and secondary outcomes will be tested by comparing results between the intervention groups, adjusting for baseline values. DISCUSSION: These results will build evidence documenting the role of probiotics on running endurance performance and physiological responses to exercise in non-elite athletes. Understanding the potential mechanisms of probiotic effects and how they mitigate the intestinal or immune discomforts caused by running could provide additional strategy means to help runners improve their performance. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04588142 . Posted on October 19, 2020. PROTOCOL VERSION: July 2, 2021, version 1.2.

Dutch listeners' perception of English lexical stress: A cue-weighting approach.

We investigate whether acoustic cue weightings are transferred from the native language to the second language [research question 1 (RQ1)], how cue weightings change with increasing second-language proficiency (RQ2), and whether individual cues are used independently or together in the second language (RQ3). Vowel reduction is a strong cue to lexical stress in English but not Dutch. Native English listeners and Dutch second-language learners of English completed a cue-weighting stress perception experiment. Participants heard sentence-final pitch-accented auditory stimuli and identified them as DEsert (initial stress) or deSSERT (final stress). The stimuli were manipulated in seven steps from initial to final stress, manipulating two dimensions at a time: vowel quality and pitch, vowel quality and duration, and pitch and duration (other dimensions neutralized). Dutch listeners relied less on vowel quality and more on pitch than English listeners, with Dutch listeners' sensitivity to vowel quality increasing with English proficiency but their sensitivity to pitch not varying with proficiency; Dutch listeners evidenced similar or weaker reliance on duration than did English listeners, and their sensitivity to duration increased with proficiency; and Dutch listeners' use of pitch and duration were positively related. These results provide general support for a cue-based transfer approach to the perception of lexical stress.

Efficacy of a Multi-Strain Probiotic Formulation in Pediatric Populations: A Comprehensive Review of Clinical Studies.

A probiotic formulation combining Lactobacillus helveticus Rosell®-52, Bifidobacterium infantis Rosell®-33, and Bifidobacterium bifidum Rosell®-71 with fructooligosaccharides, first commercialized in China, has been sold in over 28 countries since 2002. Clinical studies with this blend of strains were conducted mainly in pediatric populations, and most were published in non-English journals. This comprehensive review summarizes the clinical studies in infants and children to evaluate the efficacy of this probiotic for pediatric indications. Literature searches for pediatric studies on Biostime® or Probiokid® (non-commercial name) in 6 international and Chinese databases identified 28 studies, which were classified by indications. Twelve studies show that the probiotic significantly increases the efficacy of standard diarrhea treatment regardless of etiology, reducing the risk of unresolved diarrhea (RR 0.31 [0.23; 0.42]; p < 0.0001) by 69%. In eight studies, the probiotic enhanced immune defenses, assessed by levels of various immune competence and mucosal immunity markers (six studies), and reduced the incidence of common infections (two studies). The probiotic improved iron deficiency anemia treatment efficacy (three studies), reducing the risk of unresolved anemia by 49% (RR 0.51 [0.28; 0.92]; p = 0.0263) and significantly reducing treatment side effects by 47% (RR 0.53 [0.37; 0.77]; p = 0.0009). Other studies support further investigation into this probiotic for oral candidiasis, eczema, feeding intolerance in premature babies, or hyperbilirubinemia in newborns.

How to objectively assess and observe maladaptive pain behaviors in clinical rehabilitation: a systematic search and review.

BACKGROUND: Cognitive-affective factors influence the perception of pain and disability. These factors can lead to pain behaviors (PB) that can persist and become maladaptive. These maladaptive PB will further increase the risk of chronicity or persistence of symptoms and disability. Thus, clinicians must be prepared to recognize maladaptive PB in a clinical context. To date, in the context of assessment in a rehabilitation setting, PB in clinical settings are poorly documented. The main objective of this study was to identify direct observation methods and critically appraise them in order to propose recommendations for practice. As a secondary objective, we explored and extracted the different observable PB that patients could exhibit and that clinicians could observe. METHODS: We conducted a comprehensive review on four databases with a generic search strategy in order to obtain the largest range of PB. For the first objective, a two-step critical appraisal used clinical criteria (from qualitative studies on barriers to implement routine measures) and psychometric criteria (from Brink and Louw critical appraisal tool) to determine which observation methods could be recommended for clinical practice. For the second objective, we extracted PB found in the literature to list potential PB that patients could exhibit, and clinicians could observe. RESULTS: From the 3362 retrieved studies, 47 met the inclusion criteria for the first objective. The clinical criteria allowed us to select three observation methods. After the psychometric step, two observation methods were retained and recommended for clinical practice: the Behavioral Avoidance Test-Back Pain (BAT-Back) and the Pain Behaviour Scale (PaBS). For the second objective, 107 studies met the inclusion criteria. The extraction of the PB allowed us to list a large range of PB and classify the data in 7 categories of PB. CONCLUSION: Our results allowed us to recommend two observation methods for clinical practice. However, these methods have limitations and are validated only in chronic low back pain populations. With the extraction of PB presented in the literature, we contribute to better prepare clinicians to recognize PB in all patients who are experiencing pain.

Safety and Effect of a Low- and High-Dose Multi-Strain Probiotic Supplement on Microbiota in a General Adult Population: A Randomized, Double-Blind, Placebo-Controlled Study.

Few studies have focused on dose-response analyses of multi-strain probiotics in the general adult population. This study aimed at comparing how a low- and high-dose of a multi-strain probiotic supplement (containing Lactobacillus helveticus R0052, Lactobacillus rhamnosus R0011, Lactobacillus casei R0215, Pediococcus acidilactici R1001, Bifidobacterium breve R0070, Bifidobacterium longum ssp. longum BB536, Lactobacillus plantarum R1012, Lactococcus lactis ssp. lactis R1058) affected microbiota composition, transit persistence and safety in adults. After a 7-d baseline, participants were randomized to receive capsules containing 5 or 25 billion CFU, or placebo daily for 28 days, followed by a 7-d washout. Digestive health and general wellness were assessed. Fecal microbiota composition was analyzed using 16S rRNA gene amplicon sequencing and strain persistence, by qPCR. Participants' gastrointestinal and general wellbeing were unaffected. No adverse events were associated with either dose. Supplemented strains contributed to the Lactobacillus and Bifidobacterium genera detected in stool, with 0.40 ± 0.11% and 0.51 ± 0.26%, respectively, in the high-dose group. Strain-specific qPCR assays revealed variable levels of post-intervention persistence between strains. Sequencing and composition analyses using the 16S V4 region revealed a decrease in Holdemania and increase in Bacteroidales. The formulation was well tolerated in this sample of the general adult population, even at the higher dose. The strains appear to have influenced microbiota composition minimally, as expected in the absence of dysbiosis, and consistently with the dose administered. Overall, the results provide a rationale to study the effects this formulation on microbiota composition in individuals exhibiting dysbiosis associated with metabolic disorders or obesity.

The effects of psychobiotics on the microbiota-gut-brain axis in early-life stress and neuropsychiatric disorders.

Psychobiotics are considered among potential avenues for modulating the bidirectional communication between the gastrointestinal tract and central nervous system, defined as the microbiota-gut-brain axis (MGBA). Even though causality has not yet been established, intestinal dysbiosis has emerged as a hallmark of several diseases, including neuropsychiatric disorders (NPDs). The fact that the microbiota and central nervous system are co-developing during the first years of life has provided a paradigm suggesting a potential role of psychobiotics for earlier interventions. Studies in animal models of early-life stress (ELS) have shown that they can counteract the pervasive effects of stress during this crucial developmental period, and rescue behavioral symptoms related to anxiety and depression later in life. In humans, evidence from clinical studies on the efficacy of psychobiotics at improving mental outcomes in most NPDs remain limited, except for major depressive disorder for which more studies are available. Consequently, the beneficial effect of psychobiotics on depression-related outcomes in adults are becoming clearer. While the specific mechanisms at play remain elusive, the effect of psychobiotics are generally considered to involve the hypothalamic-pituitary-adrenal axis, intestinal permeability, and inflammation. It is anticipated that future clinical studies will explore the potential role of psychobiotics at mitigating the risk developing NPDs in vulnerable individuals or in the context of childhood adversity. However, such studies remain challenging at present in terms of design and target populations; the profound impact of stress on the proper development of the MGBA during the first year of life is becoming increasingly recognized, but the trajectories post-ELS in humans and the mechanisms by which stress affects the susceptibility to various NPDs are still ill-defined. As psychobiotics are likely to exert both shared and specific mechanisms, a better definition of target subpopulations would allow to tailor psychobiotics selection by aligning mechanistic properties with known pathophysiological mechanisms or risk factors. Here we review the available evidence from clinical and preclinical studies supporting a role for psychobiotics at ameliorating depression-related outcomes, highlighting the knowledge gaps and challenges associated with conducting longitudinal studies to address outstanding key questions in the field.

Criteria to Qualify Microorganisms as "Probiotic" in Foods and Dietary Supplements.

Still relevant after 19 years, the FAO/WHO definition of probiotics can be translated into four simple and pragmatic criteria allowing one to conclude if specific strains of microorganisms qualify as a probiotic for use in foods and dietary supplements. Probiotic strains must be (i) sufficiently characterized; (ii) safe for the intended use; (iii) supported by at least one positive human clinical trial conducted according to generally accepted scientific standards or as per recommendations and provisions of local/national authorities when applicable; and (iv) alive in the product at an efficacious dose throughout shelf life. We provide clarity and detail how each of these four criteria can be assessed. The wide adoption of these criteria is necessary to ensure the proper use of the word probiotic in scientific publications, on product labels, and in communications with regulators and the general public.

Bifidobacterium longum R0175 attenuates post-myocardial infarction depressive-like behaviour in rats.

Caspase-3 activation in the limbic system and depressive-like symptoms are observed after an acute myocardial infarction (MI) and studies suggest that inflammation may play a significant role. Combined treatment with the probiotic strains Bifidobacterium longum and Lactobacillus helveticus in rats has been shown to attenuate caspase-3 activation and depressive-like behaviour together with a reduction in pro-inflammatory cytokines. The present study was designed to determine the respective contribution of these two strains on caspase-3 activity in the limbic system and on depressive-like behaviour. Sprague-Dawley rats were assigned to one of four groups: Vehicle, L. helveticus R0052, B. longum R0175 and L. salivarius HA-118, administered orally for 14 days (109CFU daily) before inducing MI by occlusion of the left anterior descending artery for 40 min followed by 14 days of reperfusion. Animals were then tested for socialisation, passive avoidance and forced swim test to assess depressive-like behaviour. At day 18 the animals were sacrificed; infarct size was estimated, plasma C-reactive protein concentration and brain caspase-3 activity were measured. Results indicated that infarct size did not vary across the different treatments. Rats treated with B. longum spent more time socializing, learned more rapidly the passive avoidance test and spent less time immobile in the forced swim test compared to the vehicle groups. Caspase-3 activity and plasma C-reactive protein concentrations were reduced in the lateral and medial amygdala as well as in the dentate gyrus of B. longum-supplemented animals. The only significant effect in the two groups receiving Lactobacilli compared to vehicle was that rats receiving L. salivarius learned more rapidly in the step-down passive avoidance test. In conclusion, most of the beneficial effects that we previously reported with the combination of two probiotic strains in our experimentation regarding post-myocardial infarction depression are related to Bifidobacterium longum.

Syntactic Cues Take Precedence Over Distributional Cues in Native and Non-Native Speech Segmentation.

This study investigates whether syntactic cues take precedence over distributional cues in native and non-native speech segmentation by examining native and non-native speech segmentation in potential French-liaison contexts. Native French listeners and English-speaking second-language learners of French completed a visual-world eye-tracking experiment. Half the stimuli contained the pivotal consonant /t/, a frequent word onset but infrequent liaison consonant, and half contained /z/, a frequent liaison consonant but rare word onset. In the adjective-noun condition (permitting liaison), participants heard a consonant-initial target (e.g., le petit tatoué; le fameux zélé) that was temporarily ambiguous at the segmental level with a vowel-initial competitor (e.g., le petit [t]athée; le fameux [z]élu); in the noun-adjective condition (not permitting liaison), they heard a consonant-initial target (e.g., le client tatoué; le Français zélé) that was not temporarily ambiguous with a vowel-initial competitor (e.g., le client [*t]athée; le Français [*z]élu). Growth-curve analyses revealed that syntactic context modulated both groups' fixations (noun-adjective > adjective-noun), and pivotal consonant modulated both groups' fixations (/t/ > /z/) only in the adjective-noun condition, with the effect of the consonant decreasing in more proficient French learners. These results suggest that syntactic cues override distributional cues in the segmentation of French words in potential liaison contexts.

Experience with a second language affects the use of fundamental frequency in speech segmentation.

This study investigates whether listeners' experience with a second language learned later in life affects their use of fundamental frequency (F0) as a cue to word boundaries in the segmentation of an artificial language (AL), particularly when the cues to word boundaries conflict between the first language (L1) and second language (L2). F0 signals phrase-final (and thus word-final) boundaries in French but word-initial boundaries in English. Participants were functionally monolingual French listeners, functionally monolingual English listeners, bilingual L1-English L2-French listeners, and bilingual L1-French L2-English listeners. They completed the AL-segmentation task with F0 signaling word-final boundaries or without prosodic cues to word boundaries (monolingual groups only). After listening to the AL, participants completed a forced-choice word-identification task in which the foils were either non-words or part-words. The results show that the monolingual French listeners, but not the monolingual English listeners, performed better in the presence of F0 cues than in the absence of such cues. Moreover, bilingual status modulated listeners' use of F0 cues to word-final boundaries, with bilingual French listeners performing less accurately than monolingual French listeners on both word types but with bilingual English listeners performing more accurately than monolingual English listeners on non-words. These findings not only confirm that speech segmentation is modulated by the L1, but also newly demonstrate that listeners' experience with the L2 (French or English) affects their use of F0 cues in speech segmentation. This suggests that listeners' use of prosodic cues to word boundaries is adaptive and non-selective, and can change as a function of language experience.

Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function.

Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analyzed Taz in vivo and ex vivo in comparison with Yap. Small interfering RNA knockdown or retroviral-mediated expression of wild-type human or constitutively active TAZ mutants in satellite cells showed that TAZ promoted proliferation, a function shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene Wwtr1-/- ) knockout mice, there were no overt effects on regeneration. Conversely, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapfl °x/fl °x :Rosa26Lacz mice produced a regeneration deficit. To identify potential mechanisms, microarray analysis showed many common TAZ/YAP target genes, but TAZ also regulates some genes independently of YAP, including myogenic genes such as Pax7, Myf5, and Myod1 (ArrayExpress-E-MTAB-5395). Proteomic analysis revealed many novel binding partners of TAZ/YAP in myogenic cells, but TAZ also interacts with proteins distinct from YAP that are often involved in myogenesis and aspects of cytoskeleton organization (ProteomeXchange-PXD005751). Neither TAZ nor YAP bind members of the Wnt destruction complex but both regulated expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to enhance myogenic differentiation. Stem Cells 2017;35:1958-1972.

Effects of the Native Language on the Learning of Fundamental Frequency in Second-Language Speech Segmentation.

This study investigates whether the learning of prosodic cues to word boundaries in speech segmentation is more difficult if the native and second/foreign languages (L1 and L2) have similar (though non-identical) prosodies than if they have markedly different prosodies (Prosodic-Learning Interference Hypothesis). It does so by comparing French, Korean, and English listeners' use of fundamental-frequency (F0) rise as a cue to word-final boundaries in French. F0 rise signals phrase-final boundaries in French and Korean but word-initial boundaries in English. Korean-speaking and English-speaking L2 learners of French, who were matched in their French proficiency and French experience, and native French listeners completed a visual-world eye-tracking experiment in which they recognized words whose final boundary was or was not cued by an increase in F0. The results showed that Korean listeners had greater difficulty using F0 rise as a cue to word-final boundaries in French than French and English listeners. This suggests that L1-L2 prosodic similarity can make the learning of an L2 segmentation cue difficult, in line with the proposed Prosodic-Learning Interference Hypothesis. We consider mechanisms that may underlie this difficulty and discuss the implications of our findings for understanding listeners' phonological encoding of L2 words.

The Hippo signal transduction network for exercise physiologists.

The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6. Consequently, exercise should alter Hippo signaling in several organs to mediate at least some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression in muscle fibers has been shown to promote a fast-to-slow fiber type switch, whereas Yap in muscle fibers and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte adaptations, respectively. Finally, genome-wide association studies in humans have linked the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 to body height, which is a key factor in sports.

The Hippo signal transduction pathway in soft tissue sarcomas.

Sarcomas are rare cancers (≈1% of all solid tumours) usually of mesenchymal origin. Here, we review evidence implicating the Hippo pathway in soft tissue sarcomas. Several transgenic mouse models of Hippo pathway members (Nf2, Mob1, LATS1 and YAP1 mutants) develop various types of sarcoma. Despite that, Hippo member genes are rarely point mutated in human sarcomas. Instead, WWTR1-CAMTA1 and YAP1-TFE3 fusion genes are found in almost all cases of epithelioid haemangioendothelioma. Also copy number gains of YAP1 and other Hippo members occur at low frequencies but the most likely cause of perturbed Hippo signalling in sarcoma is the cross-talk with commonly mutated cancer genes such as KRAS, PIK3CA, CTNNB1 or FBXW7. Current Hippo pathway-targeting drugs include compounds that target the interaction between YAP and TEAD G protein-coupled receptors (GPCR) and the mevalonate pathway (e.g. statins). Given that many Hippo pathway-modulating drugs are already used in patients, this could lead to early clinical trials testing their efficacy in different types of sarcoma.

The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation.

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.