Biology subjects

hu, x.

Publications and source records attributed to hu, x..

4 recordsLinked to original sources

bioRxiv2025

REST elevation-dependent chromatin remodeling and alternative Grk6 transcript synthesis hyperactivates Cxcr4-Sdf1 signaling in cerebellar granule cell progenitors

RE1 Silencing Transcription Factor (REST) is a repressor of transcriptional initiation of genes involved in neurogenesis. Here, we show that conditional REST elevation in cerebellar granule cell progenitors (CGNPs) of RESTTG mice perturbed foliation, increased cell migration, and sustained C-X-C motif receptor 4 (Cxcr4) signaling, a pathway key to postnatal CGNP migration. Mechanistic studies uncovered a novel role for REST in controlling transcript diversity and exon skipping in CGNPs. Alternative transcript expression was detected in known Cxcr4 signaling regulator, G-protein-coupled receptor kinase-6 (Grk6). Further analysis of Grk6s isoform expression revealed an upregulation of a transcript lacking exon 10a (Grk6-207) in RESTTG CGNPs. Grk6-207 expression in wildtype CGNPs hyperactivated Cxcr4 signaling and increased chemotaxis. Structural modeling of Grk6-207 predicted changes in active site conformation and interactions with Cxcr4 and {beta}-Arrestin-1, supporting impairment of Cxcr4 signaling desensitization. Interestingly, REST elevation promoted increased chromatin accessibility at the exon10a-10b junction and exon 10a exclusion. Integrated multiomic analyses identified the enhancer of zeste (Ezh2) as a potential mediator of alternative transcript generation which demonstrated increased occupancy at the exon10a-10b locus in RESTTG CGNPs. Pharmacological inhibition of Ezh2 downregulated Grk6-207, confirming a role for Ezh2 in Grk6 exon10a exclusion and the increased migration in RESTTG CGNPs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/682654v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@166db32org.highwire.dtl.DTLVardef@1c0c5e0org.highwire.dtl.DTLVardef@ff2d6borg.highwire.dtl.DTLVardef@fed170_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Soluble E-cadherin Drives Brain Metastasis in Inflammatory Breast Cancer

The brain is a common site of relapse in inflammatory breast cancer (IBC), an E-cadherin positive, aggressive form of breast cancer. We found that elevated serum levels of soluble E-cadherin (sEcad), an 80-kDa fragment of E-cadherin, in patients with metastatic IBC correlated with poorer outcomes and increased rates of brain metastases. In our effort to understand the underlying mechanism, we discovered that sEcad binds to XIAP, an inhibitor of cell death, activating the pro-survival NF-k{beta} signaling in tumor cells. We also discovered that sEcad affects the tumor cell microenvironment by enhancing cancer cell adhesion to endothelial cells and inducing reactive astrocytosis in the brain. In addition, we found that sEcad-mediated reactive astrocytosis relies on the CXCL1/CXCL8-CXCR2 axis and treatment with a brain-permeable CXCR2 antagonist reduced brain metastatic burden and prolonged survival. These findings implicate sEcad in brain metastasis and provide new insights into potential therapeutic targets for IBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/660428v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@10a7c47org.highwire.dtl.DTLVardef@1653278org.highwire.dtl.DTLVardef@d4787corg.highwire.dtl.DTLVardef@132489b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHigh serum sEcad levels correlate clinically with poor survival outcomes and development of brain metastasis C_LIO_LIsEcad drives IBC brain metastasis growth in mouse models C_LIO_LIsEcad binds XIAP to activate NFkB and promote anoikis resistance and invasion of IBC cells C_LIO_LIsEcad activates reactive astrocytes and induces CXCR2 expression on tumor cells in vitro and in vivo C_LIO_LICXCR2-IN-1, a brain-permeable CXCR2 antagonist, reduces metastasis and improves survival in IBC brain metastasis models C_LI

cancer biology↗

bioRxiv2024

Sec14L6 is a PS and PI4P transporter that promotes lipid droplet formation

Lipid droplets (LDs) are evolutionarily conserved organelles that are crucial for cellular metabolism. LD biogenesis and growth occurs in the ER and requires the supply of phospholipid from the ER, but the molecular basis is largely unclear. Here, we have identified Sec14L6, a unique protein of the Sec14 family, as a PS/PI4P transporter required for LD biogenesis. Sec14L6 knockout (KO) greatly reduces the number of LDs that can be rescued by wild-type rather than lipid transfer-defective Sec14L6 mutants. We found that Sec14L6 directly interacts with ACSL3, and that this interaction facilitates targeting of Sec14L6 to LDs and activates the PS transfer activity of Sec14L6 in vitro. We also identified PGRMC1, an ER membrane protein, as an adaptor that recruits Sec14L6 to the ER. Furthermore, depletion of Sec14L6 impairs differentiation of adipose-derived mesenchymal stem cells. Together, our study suggests that Sec14L6 transports PS and/or PI4P between the ER and LDs to promote LD formation.

cell biology↗

bioRxiv2020

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗