Biology subjects

huang, x.

Publications and source records attributed to huang, x..

3 recordsLinked to original sources

bioRxiv2024

Ligand-independent c-Met activation by HHLA2 drives hepatocellular carcinoma and predicts c-MET inhibitor efficacy

The HGF/c-Met signaling pathway facilitates the initiation, progression, and metastasis of hepatocellular carcinoma (HCC). c-Met activation, however, is complex and not solely dependent on HGF, hindering targeted therapy development. This study identifies a critical oncogenic role for HHLA2, a B7 family member, in HCC and highlights its potential as a therapeutic target. We demonstrate that HHLA2 directly interacts with and activates c-Met through N-glycosylation, triggering sustained signaling and promoting aggressive HCC features. Mechanistically, we identified the pro-tumorigenic role of HHLA2 required downstream upregulation of MMP9 and VEGFA, both implicated in tumor progression. In multiple mouse models, HHLA2 overexpression accelerated tumor progression, metastasis, and reduced liver NK cell infiltration, all of which were reversed by c-Met inhibition. In a cohort of 176 HCC patients, HHLA2 expression strongly correlated with c-Met phosphorylation, advanced tumor stage, and poor prognosis. Importantly, HHLA2 expression predicted sensitivity to c-Met inhibitors in cell lines and patient-derived organoids and could be detected in patient serum, suggesting its potential as a prognostic biomarker. Collectively, our findings reveal an HHLA2-mediated mechanism of c-Met activation and provide a strong rationale for targeting the HHLA2-c-Met axis as a novel therapeutic strategy, with HHLA2 serving as a potential prognostic biomarker. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/622557v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@8b10dforg.highwire.dtl.DTLVardef@b43dorg.highwire.dtl.DTLVardef@394c4aorg.highwire.dtl.DTLVardef@1bfbc8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Interleaved intersectional strategy enables genetic lineage tracing with enhanced specificity

BACKGROUNDDual recombinases have been increasingly employed for enhanced precision in genetic targeting. A recent study utilizing an intersectional genetic approach through dual recombinases (Dre + CreER) has revealed that endocardium-derived fibroblasts (EndoFbs) play a pivotal role in cardiac fibrosis after pressure overload. However, this intersectional strategy has limitations, primarily due to ectopic genetic labeling of non-target cells within the adult heart by the constitutively active Dre recombinase. METHODSTo address this issue, we have developed an advanced, interleaved and intersectional reporter (IIR) strategy in this study. This IIR strategy leverages an inducible CreER to prevent inadvertent Dre-rox recombination during development or disease progression by designing an interleaved reporter to allow for more specific tracing of EndoFbs. Moreover, our IIR system also incorporates Diphtheria Toxin Receptor (DTR) in targeted cells, enabling functional characterization of these cells after genetic ablation. RESULTSEndoFbs were regionally distributed in the heart during homeostasis and proliferated preferentially in response to pressure overload, leading to cardiac fibrosis in defined regions. The IIR strategy enables the tracing of EndoFbs with a more prominent regional pattern and facilitates genetic ablation of EndoFbs through DT injection. In addition, we have applied this IIR strategy to specifically target fibroblasts derived from the epicardium (EpiFbs). Genetic lineage tracing of EpiFb reveals that their distribution pattern is complementary to that of EndoFbs in the adult heart. When a substantial number of EpiFbs were genetically ablated, EndoFbs could replace the loss of EpiFbs in some specific regions of hearts. CONCLUSIONSThe IIR strategy refines the precision of genetic lineage tracing while still employing the constitutively active Dre recombinase in tandem with inducible Cre. EndoFbs and EpiFbs are complementary in their distribution pattern in the heart, where EndoFbs have the potential to replace the loss of EpiFbs in some regions.

genetics↗

bioRxiv2022

TME induced TRAIL secretion from engineered macrophages for anti-tumor therapy

Capacity of tumor niche chemotaxis and long-term persistency making macrophage as great vehicles for anti-tumor factor delivery. Macrophages-based delivery of chemokines or cytokines have been tested for tissue homeostasis and cancer repression. TRAIL as a promising anti-tumor cytokine, made little clinical progress due to limited stability and off-target toxicity. Here we engineered macrophages with tumor micro-environment (TME)-induced trimerized CP1-TRAIL secretion under the TME specific promoter Arg1 (Tri-TRAIL-iM). The Tri-TRAIL-iM cells displayed high specific inducible activity in both cell-based co-culture assay and in tumor baring mice models. Compared to normal TRAIL over-expressed macrophages under none-inducible promoter, Tri-TRAIL-iM infiltrated to tumor sites and showed superior apoptosis induction of cancer cells and tumor growth repression as well as less systemic side effect. This inducible delivery TRAIL strategy can be effectively further applied in clinical studies and can be coupled with other engineered methods to maximize the therapeutic outcomes for solid tumors.

cancer biology↗