Ava M. Boston

Bio: Ava M. Boston is an academic researcher from Clark Atlanta University. The author has contributed to research in topics: Hippo signaling pathway & YAP1. The author has co-authored 1 publications.

The Hippo pathway: an emerging role in urologic cancers.

Abstract: The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer.

The Hippo pathway and its correlation with acute kidney injury

Abstract: Acute kidney injury (AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectors Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma

Abstract: Background Early detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined. Methods STs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the “early” cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced “later” canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening. Results Biopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention. Conclusions The study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

The Hippo effector YAP1/TEAD1 regulates EPHA3 expression to control cell contact and motility

Abstract: The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell-cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell-cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated by YAP1/TEAD1 of the Hippo pathway, suggesting that it is sensitive to cell contact-dependent interactions.