Biology subjects

Parrish, A. G.

Publications and source records attributed to Parrish, A. G..

4 recordsLinked to original sources

bioRxiv2025

C-terminal fusion partner activity contributes to the oncogenic functions of YAP1::TFE3

YAP1 gene fusions are found in a multitude of human tumors, are potent oncogenic drivers, and are the likely initiating tumorigenic events in these tumors. We and others have previously shown that a YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity that is resistant to inhibitory Hippo pathway signaling. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we used the RCAS/tv-a system to express eight different YAP1 gene fusions in vivo and observed significant differences in the latencies of tumors induced by the various YAP1 fusions. We observed that tumors induced by YAP1::TFE3 displayed a significantly different histomorphology compared to tumors induced by other YAP1 fusions or activated non-fusion YAP1. To assess the extent to which the functional TFE3 domains (DNA binding: leucine zipper (LZ) and basic-helix-loop-helix (bHLH); activation domain (AD)) contribute to the oncogenic functions of YAP1::TFE3, we generated several mutant variants and performed functional in vitro and in vivo assays. In vitro, mutation or deletion of the TFE3 DNA binding domains (LZ, bHLH) resulted in reduced TFE3 activity but increased YAP1 activity of YAP1::TFE3. In vivo, deletion of the LZ and bHLH domains did not result in a decrease in tumor incidence but induced the formation of more YAP1-like tumors that lacked prominent features of YAP1::TFE3-driven tumors. By contrast, loss of the TFE3 AD almost completely abrogated tumor formation. Our results suggest that the TFE3 domains significantly contribute to the oncogenic activity of YAP1::TFE3.

cancer biology↗

bioRxiv2024

Early Life Behavior Phenotypes and Cortisol Responses to Common Lab Stressors in a Cichlid Fish

The stress response is highly conserved across species, and increased glucocorticoid release (cortisol in fishes) is a key element. In the highly social cichlid fish, Burtons Mouthbrooder (Astatotilapia burtoni), stress axis activity is associated with juvenile social behavior and status, and it mediates early-life social effects, yet little is known about early-life stress physiology. We measured water-borne cortisol, a non-invasive method, in juveniles less than 1-week old. We first tested whether juveniles habituate to the beaker confinement necessary for sample collection. Repeated exposure to a beaker did not affect cortisol compared to handled and unhandled controls. In a separate cohort, we next measured behavior in an open field exploration and social cue investigation, followed by a test of whether common lab stressors elevated cortisol. Controls were undisturbed in a collection beaker (90 min). For the stressor treatments, we collected three sequential samples (30 min each) to try and quantify stress response peak and recovery; however, we found no effect of time. Stressors included handling, brief net confinement, and brief gentle movement. These stressors led to a significant increase in cortisol, with the highest levels resulting from confinement. The behavior tests revealed a bold-shy axis across both tests, describing the behavior of most individuals. A distinct group of socially-motivated juveniles showed a dramatic switch, staying in the territory during the open field but leaving to investigate the social cue. We found no associations between behavior and cortisol response. This work provides insight into early-life behavior and stress axis development and function. HighlightsO_LIAstatotilapia burtoni under 1-week old did not habituate to beaker confinement C_LIO_LIYoung juveniles displayed bold/shy or socially-motivated behavior phenotypes C_LIO_LICortisol increased in response to lab stressors: handling, confinement, and movement C_LIO_LIIndividual variation in cortisol establishes an expected hormone range for this age C_LIO_LIJuvenile cortisol did not correlate with behavior or differ by behavior phenotype C_LI

physiology↗

bioRxiv2024

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.

Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

molecular biology↗

bioRxiv2024

Development of a series of genetically engineered NTRK fusion-driven pediatric-type high-grade glioma mouse models

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.

cancer biology↗