Browsing by Author "Jiang, Hua"

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    Cdc42-mediated supracellular cytoskeleton induced cancer cell migration under low shear stress
    (Elsevier, 2019-10) Liu, Lingling; Jiang, Hua; Zhao, Wei; Meng, Yao; Li, Ji; Huang, Tongwei; Sun, Jinghui; Pediatrics, School of Medicine
    Tumor microenvironment is composed of biological, chemical and physical factors. Mechanical factors are more and more focused these years. Therefore, mimicking mechanical factors' contribution to cancer cell malignancy will greatly improve the advance in this field. Although the induced malignant behaviors are present under many stimuli such as growth or inflammatory factors, the cell key physical migration mechanisms are still missing. In this study, we identify that low shear stress significantly promotes the formation of needle-shaped membrane protrusions, which is called filopodia and important for the sense and interact of a cell with extracellular matrix in the tumor microenvironment. Under low shear stress, the migration is promoted while it is inhibited in the presence of ROCK inhibitor Y27632, which could abolish the F-actin network. Using cell imaging, we further unravel that key to these protrusions is Cell division cycle 42 (Cdc42) dependent. After Cdc42 activation, the filopodia is more and longer, acting as massagers to pass the information from a cell to the microenvironment for its malignant phenotype. In the Cdc42 inhibition, the filopodia is greatly reduced. Moreover, small GTPases Cdc42 rather than Rac1 and Rho directly controls the filopodia formation. Our work highlights that low shear stress and Cdc42 activation are sufficient to promote filopodia formation, it not only points out the novel structure for cancer progression but also provides the experimental physical basis for the efficient drug anti-cancer strategies.
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    Granzyme A–producing T helper cells are critical for acute graft-versus-host disease
    (American Society for Clinical Investigation, 2020-08-18) Park, Sungtae; Griesenauer, Brad; Jiang, Hua; Adom, Djamilatou; Mehrpouya-Bahrami, Pegah; Chakravorty, Srishti; Kazemian, Majid; Imam, Tanbeena; Srivastava, Rajneesh; Hayes, Tristan A.; Pardo, Julian; Janga, Sarath Chandra; Paczesny, Sophie; Kaplan, Mark H.; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
    Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.
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    Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature
    (Frontiers, 2021) Fu, Denggang; Zhang, Biyu; Wu, Shiyong; Zhang, Yinghua; Xie, Jingwu; Ning, Wangbin; Jiang, Hua; Pediatrics, School of Medicine
    Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies that has an unfavorable outcome and a high rate of relapse. Autophagy plays a vital role in the development of and therapeutic responses to leukemia. This study identifies a potential autophagy-related signature to monitor the prognoses of patients of AML. Transcriptomic profiles of AML patients (GSE37642) with the relevant clinical information were downloaded from Gene Expression Omnibus (GEO) as the training set while TCGA-AML and GSE12417 were used as validation cohorts. Univariate regression analyses and multivariate stepwise Cox regression analysis were respectively applied to identify the autophagy-related signature. The univariate Cox regression analysis identified 32 autophagy-related genes (ARGs) that were significantly associated with the overall survival (OS) of the patients, and were mainly rich in signaling pathways for autophagy, p53, AMPK, and TNF. A prognostic signature that comprised eight ARGs (BAG3, CALCOCO2, CAMKK2, CANX, DAPK1, P4HB, TSC2, and ULK1) and had good predictive capacity was established by LASSO–Cox stepwise regression analysis. High-risk patients were found to have significantly shorter OS than patients in low-risk group. The signature can be used as an independent prognostic predictor after adjusting for clinicopathological parameters, and was validated on two external AML sets. Differentially expressed genes analyzed in two groups were involved in inflammatory and immune signaling pathways. An analysis of tumor-infiltrating immune cells confirmed that high-risk patients had a strong immunosuppressive microenvironment. Potential druggable OS-related ARGs were then investigated through protein–drug interactions. This study provides a systematic analysis of ARGs and develops an OS-related prognostic predictor for AML patients. Further work is needed to verify its clinical utility and identify the underlying molecular mechanisms in AML.
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    ST2 as checkpoint target for colorectal cancer immunotherapy
    (American Society for Clinical Investigation, 2020-05-07) Jeught, Kevin Van der; Sun, Yifan; Fang, Yuanzhang; Zhou, Zhuolong; Jiang, Hua; Yu, Tao; Yang, Jinfeng; Kamocka, Malgorzata M.; So, Ka Man; Li, Yujing; Eyvani, Haniyeh; Sandusky, George E.; Frieden, Michael; Braun, Harald; Beyaert, Rudi; He, Xiaoming; Zhang, Xinna; Zhang, Chi; Paczesny, Sophie; Lu, Xiongbin; Pediatrics, School of Medicine
    Immune checkpoint blockade immunotherapy delivers promising clinical results in colorectal cancer (CRC). However, only a fraction of cancer patients develop durable responses. The tumor microenvironment (TME) negatively impacts tumor immunity and subsequently clinical outcomes. Therefore, there is a need to identify other checkpoint targets associated with the TME. Early-onset factors secreted by stromal cells as well as tumor cells often help recruit immune cells to the TME, among which are alarmins such as IL-33. The only known receptor for IL-33 is stimulation 2 (ST2). Here we demonstrated that high ST2 expression is associated with poor survival and is correlated with low CD8+ T cell cytotoxicity in CRC patients. ST2 is particularly expressed in tumor-associated macrophages (TAMs). In preclinical models of CRC, we demonstrated that ST2-expressing TAMs (ST2+ TAMs) were recruited into the tumor via CXCR3 expression and exacerbated the immunosuppressive TME; and that combination of ST2 depletion using ST2-KO mice with anti–programmed death 1 treatment resulted in profound growth inhibition of CRC. Finally, using the IL-33trap fusion protein, we suppressed CRC tumor growth and decreased tumor-infiltrating ST2+ TAMs. Together, our findings suggest that ST2 could serve as a potential checkpoint target for CRC immunotherapy.
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    ST2/MyD88 deficiency protects mice against aGVHD and spares T-regulatory cells
    (American Association of Immunologists, 2020-04-12) Griesenauer, Brad; Jiang, Hua; Yang, Jinfeng; Zhang, Jilu; Ramadan, Abdulraouf M.; Egbosiuba, Jane; Campa, Khaled; Paczesny, Sophie; Medicine, School of Medicine
    Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD88-/- CD4 T cells. Transplanting donor MyD88-/- conventional T cells (Tcons) with wild-type (WT) or MyD88-/- regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD88-/- CD4 T cells from the intestine 10 d post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, Batf, and Jak2 Transplanting donor ST2-/- Tcons with WT or ST2-/- Tregs showed a similar phenotype with what we observed when using donor MyD88-/- Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.