Biology subjects

Qian, V.

Publications and source records attributed to Qian, V..

3 recordsLinked to original sources

bioRxiv2025

Tissue Kallikrein 1 cleaves complement factor C3 and activates the alternative complement pathway

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), characterized by microvascular endothelial damage and severe renal injury, negatively affects HSCT survivorship with high mortality and long-term renal morbidity. After HSCT, innate immunity and inflammation are often dysregulated. The alternative complement pathway (AP) of the innate immune system is overactivated in HSCT-TMA, but the mechanisms of its initiation are poorly described. Complement component C3 of the AP can be cleaved by proteases outside of the AP. Because mRNA expression of tissue kallikrein 1 (KLK1), an inflammatory serine protease that produces kinins, has been found to be markedly elevated in the renal endothelium of inflamed mice, we hypothesized that increased KLK1 activity during inflammation contributes to AP overactivation and endothelial injury in HSCT-TMA. We assessed AP activation, KLK1 activity, endothelial injury, and renal function in HSCT-TMA experimental models and disease settings and investigated C3 cleavage and AP activation by KLK1. We found that patients with HSCT-TMA had significantly increased AP activation and decreased KLK1 inactivation at TMA diagnosis compared to pre-HSCT. Mice challenged with HSCT-TMA triggers cyclosporine A (CsA) and lipopolysaccharide (LPS) exhibited increased AP activation, renal endothelial injury, and impaired renal function in the setting of decreased KLK1 inactivation. We further demonstrated that KLK1 cleaved AP component C3 to C3b that functionally activated the AP. Our data indicate a noncanonical mechanism for AP activation by KLK1 in settings of HSCT-TMA. Key PointsO_LITissue kallikrein (KLK1) functionally cleaves complement factor C3. C_LIO_LIReduced KLK1 inhibition is associated with activation of the alternative pathway of complement. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/674260v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@8f260aorg.highwire.dtl.DTLVardef@a6511org.highwire.dtl.DTLVardef@7160f6org.highwire.dtl.DTLVardef@194d36d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO HSCT-TMA triggers (e.g. inflammation, immunosuppression) upregulate expression of the inflammatory serine protease KLK1, which cleaves C3 to initiate AP activation and amplification, leading to renal endothelial injury. Created with BioRender.com under its Academic License Terms with Baylor College of Medicine. C_FIG

molecular biology↗

bioRxiv2023

From breast cancer cell homing to the onset of early bone metastasis: dynamic bone (re)modeling as a driver of osteolytic disease

Breast cancer often metastasizes to bone causing osteolytic lesions. Structural and biophysical changes are rarely studied, yet are hypothesized to influence metastatic progression. Here, we developed a mouse model of early bone metastasis and multimodal 3D imaging to quantify cancer cell homing, dynamic bone (re)modeling and onset of bone metastasis. Using 3D light sheet fluorescence microscopy, we show eGFP+ cancer cells and small clusters in 3D (intact) bones. We detect early bone lesions using time-lapse in vivo microCT and reveal altered bone (re)modeling in absence of detectable lesions. With a new microCT image analysis tool, we detect and track the growth of early bone lesions over time. We show that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study provides novel insights of dynamic bone (re)modeling as a driver during the early phase of metastasis.

bioengineering↗

bioRxiv2019

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Breast tumor heterogeneity is a major impediment to oncotherapy. Tumor cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk tumors precludes efficient therapeutic and diagnostic management of breast cancer. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the role of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN), as a molecular marker of aggressive cancers. High-risk invasive cell lines generated from relatively less invasive MCF7 and MDA-MB-468 breast cancer cells by long-term TGF-{beta} treatment and chemoresistance demonstrated hybrid epithelial-mesenchymal phenotype, enhanced motility, and significantly elevated EDB-FN levels in 2D- and 3D-cultures. To determine if EDB-FN could serve as a therapy-predictive marker, the invasive cell lines were treated with MK2206-HCl, a pan-AKT inhibitor. Phospho-AKT depletion reduced EMT and invasion of the populations, with a concomitant decrease in EDB-FN expression, partly through the phosphoAKT-SRp55 pathway, demonstrating that EDB-FN expression is strongly associated with high-risk breast cancer. EDB-FN is a promising molecular marker for accurate detection, differential diagnosis, and non-invasive therapeutic surveillance of aggressive breast cancer.\n\nSummary StatementDynamic changes in invasive properties of breast cancer cells directly influence extradomain-B fibronectin levels, suggesting its potential role as a molecular marker for active surveillance and therapeutic monitoring of breast cancer.

cancer biology↗