Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor

BackgroundAtypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown.ProcedureWe performed high‐throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real‐time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells.ResultsTEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4’s co‐activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4‐mutated cells.ConclusionsWe report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137309/1/pbc26398_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137309/2/pbc26398.pd

Differentiating comorbidities and predicting prognosis in idiopathic normal pressure hydrocephalus using cerebrospinal fluid biomarkers: a review

Idiopathic normal pressure hydrocephalus (iNPH) is a condition resulting from impaired cerebrospinal fluid (CSF) absorption and excretion characterized by a triad of symptoms comprising dementia, gait disturbance (impaired trunk balance), and urinary incontinence. CSF biomarkers not only assist in diagnosis but are also important for analyzing the pathology and understanding appropriate treatment indications. As the neuropathological findings characteristic of iNPH have yet to be defined, there remains no method to diagnose iNPH with 100% sensitivity and specificity. Neurotoxic proteins are assumed to be involved in the neurological symptoms of iNPH, particularly the appearance of cognitive impairment. The symptoms of iNPH can be reversed by improving CSF turnover through shunting. However, early diagnosis is essential as once neurodegeneration has progressed, pathological changes become irreversible and symptom improvement is minimal, even after shunting. Combining a variety of diagnostic methods may lead to a more definitive diagnosis and accurate prediction of the prognosis following shunt treatment. Identifying comorbidities in iNPH using CSF biomarkers does not contraindicate shunting-based intervention, but does limit the improvement in symptoms it yields, and provides vital information for predicting post-treatment prognosi

Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade.

The aim of this study was to determine whether the improvement of cerebrospinal fluid (CSF) flow dynamics by CSF shunting, can suppress the oligomerization of amyloid β-peptide (Aβ), by measuring the levels of Alzheimer's disease (AD)-related proteins in the CSF before and after lumboperitoneal shunting. Lumbar CSF from 32 patients with idiopathic normal pressure hydrocephalus (iNPH) (samples were obtained before and 1 year after shunting), 15 patients with AD, and 12 normal controls was analyzed for AD-related proteins and APLP1-derived Aβ-like peptides (APL1β) (a surrogate marker for Aβ). We found that before shunting, individuals with iNPH had significantly lower levels of soluble amyloid precursor proteins (sAPP) and Aβ38 compared to patients with AD and normal controls. We divided the patients with iNPH into patients with favorable (improvement ≥ 1 on the modified Rankin Scale) and unfavorable (no improvement on the modified Rankin Scale) outcomes. Compared to the unfavorable outcome group, the favorable outcome group showed significant increases in Aβ38, 40, 42, and phosphorylated-tau levels after shunting. In contrast, there were no significant changes in the levels of APL1β25, 27, and 28 after shunting. After shunting, we observed positive correlations between sAPPα and sAPPβ, Aβ38 and 42, and APL1β25 and 28, with shifts from sAPPβ to sAPPα, from APL1β28 to 25, and from Aβ42 to 38 in all patients with iNPH. Our results suggest that Aβ production remained unchanged by the shunt procedure because the levels of sAPP and APL1β were unchanged. Moreover, the shift of Aβ from oligomer to monomer due to the shift of Aβ42 (easy to aggregate) to Aβ38 (difficult to aggregate), and the improvement of interstitial-fluid flow, could lead to increased Aβ levels in the CSF. Our findings suggest that the shunting procedure can delay intracerebral deposition of Aβ in patients with iNPH

Bar charts of patient functional status based on their mRS score.

<p>A: Distribution of patients across mRS scores before and after LPS. B: Change in the median mRS scores 1 year after LPS. Abbreviations: LPS, lumboperitoneal shunting; mRS, modified Rankin Scale.</p

Association of Alzheimer’s disease-related proteins before and after shunting.

<p>A: Association between APL1β25 and APL1β28. B: Association between Aβ38 and Aβ42. Abbreviations: pre, before lumboperitoneal shunt; post, after lumboperitoneal shunt; Aβ, amyloid β-peptide; APL1β, APLP1-derived Aβ like peptide.</p

Comparison of CSF values in patients with iNPH before and 1 year after LPS.

<p>Abbreviations: before, before lumboperitoneal shunt; after, a year after lumboperitoneal shunt; Aβ, amyloid β-peptide; AD, Alzheimer’s disease; APL1β, APLP1-derived Aβ like peptide; CSF, cerebrospinal fluid; iNPH, idiopathic normal pressure hydrocephalus; LPS, lumboperitoneal shunt; NC, normal control; NS, non-significant; p-tau, tau phosphorylated at threonine 181; sAPP, soluble amyloid precursor protein</p><p>All <i>P</i> values were obtained using the Wilcoxon test. SD values are given in parentheses.</p><p>Correlation is significant at the 0.05 level.</p><p>Comparison of CSF values in patients with iNPH before and 1 year after LPS.</p

Graph showing the relation between pre- and post-operative lumbar CSF values of individual patients with iNPH for sAPPα, sAPPβ, Aβ 38, 40, and 42, APL1β25, 27, and 28, and p-tau.

<p>Abbreviations: CSF, cerebrospinal fluid; iNPH, idiopathic normal pressure hydrocephalus; before, before lumboperitoneal shunt; after, 1 year after lumboperitoneal shunt; sAPP, soluble amyloid precursor protein; Aβ, amyloid β-peptide; APL1β, APLP1-derived Aβ like peptide; p-tau, tau phosphorylated at threonine 181.</p

Correlation between Aβ38, 40 levels, and APL1β (25, 27, and 28) in patients with iNPH before LPS.

<p>A: Association between APL1β (25, 27, and 28) and Aβ38. B: Association between APL1β (25, 27, and 28) and Aβ42. Abbreviations: Aβ, amyloid β-peptide; APL1β, APLP1-derived Aβ like peptide; iNPH, idiopathic normal pressure hydrocephalus; LPS, lumboperitoneal shunting.</p