Biology subjects

Hsu, C.-S.

Publications and source records attributed to Hsu, C.-S..

3 recordsLinked to original sources

bioRxiv2024

Distinct neuroendocrine subtypes predict treatment-induced neuroendocrine prostate cancer prognosis and provide clues for personalized treatment

Background and ObjectiveSecond-generation hormonal therapy inhibits castration-resistant prostate cancer (CRPC), but the tumor eventually recurs as neuroendocrine prostate cancer (NEPC) and turns lethal. Differentiating lineage plasticity that contributed to distinct NEPC subtypes aids in advancing treatments, particularly the recent FDA-approved 177Lu-PSMA-617 radiopharmaceutical therapy. MethodsWe integrated single-cell RNA sequencing data from fresh human CRPC cases. This comprehensive approach allowed us to identify distinct NEPC subpopulations and their respective lineage with high confidence. Key Findings and LimitationsWe uncovered N-Myc and REST as key transcription factors driving distinct neuroendocrine subtypes among 5,797 neuroendocrine-like epithelial cells in CRPC: a REST-dependent subtype (NE I), an N-Myc-dependent subtype (NE II), and a combined N-Myc/REST subtype (NE I+II). These subtypes were validated using multiplex immunofluorescence staining. Trajectory analysis of single-cell RNA sequencing data, along with multi-omics time course analysis of publicly available transcriptomic data recapitulated N-Myc and REST lineages. Additionally, we observed PSMA loss in N-Myc lineage NEPC and identified STMN1 as a biomarker for PSMA-negative subtype. We validated the prognostic value of STMN1 using the TCGA dataset and 60 in-house CRPC tissues. Given that surgery is rarely performed in advanced CRPC, leading to limited sample availability, further validation in larger cohorts is needed. Conclusions and Clinical ImplicationsAdeno-to-neuroendocrine lineage transition in prostate cancer leads to resistance to new therapies. The lethal NEPC phenotype should be revealed earlier in the disease course of patients with CRPC, providing crucial clues for personalized precision medicine.

cancer biology↗

bioRxiv2020

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

Background DYT1 dystonia is a neurological movement disorder characterized by painful sustained muscle contractions resulting in abnormal twisting and postures. In a subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in the luminal ATPases associated with various cellular activities (AAA+) protein torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (∼30-40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia.Methods To identify these modifiers, we performed whole exome sequencing of blood leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic carriers of the ΔE mutation, and an unaffected adult relative.Results A total of 264 DYT1 dystonia-associated variants (DYT1 variants) were identified in 195 genes. Consistent with the emerging view of torsinA as an important regulator of the cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found DYT1 variants in genes that encode proteins implicated in these processes. Moreover, 40 DYT1 variants were detected in 32 genes associated with neuromuscular and neuropsychiatric disorders.Conclusion The DYT1 variants described in this work represent exciting new targets for future studies designed to increase our understanding of the pathophysiology and pathogenesis of DYT1 dystonia.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2019

Association of SYNE2 variants in accelerating the progress of DYT1 early-onset isolated dystonia

DYT1 early-onset isolated dystonia (DYT1 dystonia), a rare autosomal dominant (AD) primary dystonia, is categorized as a monogenic disease. While it is a well-known AD inherited disease, the relatively low penetrance rate implicates potential modifiers in play for disease progression. In this report, an affected individual with TOR1A gene (c.907_909delGAG, p.E303del) variant, was identified along with three additional AD carriers in the family. Since we failed to find the second hit variant from TOR1A (D216H, F323_Y328del and F205I) and major binding proteins, including TOR1AIP1 and 2 or HSPA8 proteins, subsequent whole exome sequencing on the patient, the carriers and a non-carrier family member were performed to screen for candidate modifiers of TOR1A (E303del). The result reveals that this patient distinctly carries one copy of TOR1A gene (c.907_909delGAG, p.E303del) and one or two copy of SYNE2 gene (c.1721T>C, c.12001T>C, and c.12002G>A), encoding I574T, W4001R, and W4001Ter variants. We propose that these SYNE2 variants are linked to earlier disease onset in this patient by impacting the protein-protein interaction between TOR1A and SYNE2. Our study suggests SYNE2 gene maybe a culprit to lower the threshold for DYT1 dystonia progression and provides one novel gene target for further screening diagnosis of DYT1 dystonia.

genetics↗