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Browsing by Author "Liu, Lingling"
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Item Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response(Springer Nature, 2023) Gnanaprakasam, J. N. Rashida; Kushwaha, Bhavana; Liu, Lingling; Chen, Xuyong; Kang, Siwen; Wang, Tingting; Cassel, Teresa A.; Adams, Christopher M.; Higashi, Richard M.; Scott, David A.; Xin, Gang; Li, Zihai; Yang, Jun; Lane, Andrew N.; Fan, Teresa W. M.; Zhang, Ji; Wang, Ruoning; Pediatrics, School of MedicineRobust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.Item 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 MedicineTumor 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.