Tianyu Zhao

All Publications

• p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program. Cancer discovery Wang, M., Bieging-Rolett, K. T., Kaiser, A. M., Brady, C. A., Lockhart, J. H., Ferreira, S., Nguyen, K. T., Rajeevan, A., Evans, S. A., Zhao, T., Raj, N., Elkrief, A., Tischfield, S. E., Ladanyi, M., Ozawa, M. G., Bui, N. Q., Chen, C. T., Flores, E. R., Attardi, L. D. 2025

  Abstract

  Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

  View details for DOI 10.1158/2159-8290.CD-25-0525

  View details for PubMedID 41115251

• VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes NATURE COMMUNICATIONS Zhao, T., Guan, Y., Xu, C., Wang, D., Guan, J., Liu, Y. 2023; 14 (1): 8464

  Abstract

  The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth. It senses nutrient signals and adjusts cellular metabolism accordingly. Deregulation of mTORC1 has been associated with metabolic diseases, cancer, and aging. Amino acid signals are transduced to mTORC1 through sensor proteins and two protein complexes named GATOR1 and GATOR2. In this study, we identify VWCE (von Willebrand factor C and EGF domains) as a negative regulator of amino acid-dependent mTORC1 signaling. Knockdown of VWCE promotes mTORC1 activity even in the absence of amino acids. VWCE interacts with the KICSTOR complex to facilitate the recruitment of GATOR1 to the lysosomes. Bioinformatic analysis reveals that expression of VWCE is reduced in prostate cancer. More importantly, overexpression of VWCE inhibits the development of prostate cancer. Therefore, VWCE may serve as a potential therapeutic target for the treatment of prostate cancers.

  View details for DOI 10.1038/s41467-023-44241-8

  View details for Web of Science ID 001128854200011

  View details for PubMedID 38123554

  View details for PubMedCentralID PMC10733324

• A novel <i>N</i><SUP>6</SUP>-Deoxyadenine methyltransferase METL-9 modulates <i>C. elegans</i> immunity via dichotomous mechanisms CELL RESEARCH Ma, C., Xue, T., Peng, Q., Zhang, J., Guan, J., Ding, W., Li, Y., Xia, P., Zhou, L., Zhao, T., Wang, S., Quan, L., Li, C., Liu, Y. 2023; 33 (8): 628-639

  Abstract

  N6-Methyldeoxyadenine (6mA) has been rediscovered as a DNA modification with potential biological function in metazoans. However, the physiological function and regulatory mechanisms regarding the establishment, maintenance and removal of 6mA in eukaryotes are still poorly understood. Here we show that genomic 6mA levels change in response to pathogenic infection in Caenorhabditis elegans (C. elegans). We further identify METL-9 as the methyltransferase that catalyzes DNA 6mA modifications upon pathogen infection. Deficiency of METL-9 impairs the induction of innate immune response genes and renders the animals more susceptible to pathogen infection. Interestingly, METL-9 functions through both 6mA-dependent and -independent mechanisms to transcriptionally regulate innate immunity. Our findings reveal that 6mA is a functional DNA modification in immunomodulation in C. elegans.

  View details for DOI 10.1038/s41422-023-00826-y

  View details for Web of Science ID 001000157800001

  View details for PubMedID 37271765

  View details for PubMedCentralID PMC10397248

• IκBα phosphorylation and associated NF-κB activation are essential events in lymphocyte activation, proliferation, and anti-bacterial adaptive immune response of Nile tilapia DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY Li, C., Yu, J., Ai, K., Li, H., Zhang, Y., Zhao, T., Wei, X., Yang, J. 2020; 103: 103526

  Abstract

  Inhibitory protein IκBα plays a crucial role in the inflammatory process and immune response by regulating the activity of transcription factor NF-κB. In teleost, great progress has been achieved regarding NF-κB signaling for innate immunity, but whether this pathway modulates adaptive immunity, and how, remains largely unclear. In this study, after characterizing the sequence, structure, and phylogeny of Nile tilapia Oreochromis niloticus IκBα (defined as On-IκBα), we investigated the association between IκBα-regulated NF-κB activation and the lymphocyte-mediated adaptive immune response in Nile tilapia. We found that On-IκBα was evolutionarily conserved, and its mRNA was expressed widely in various tissues, with most abundance in the trunk kidney. mRNA expression of On-IκBα was significantly upregulated in spleen at both innate and adaptive immune stages after Aeromonas hydrophila infection. Moreover, phosphorylation of On-IκBα and the downstream On-NF-κB p65 was obviously elevated in spleen leukocytes at 3, 5, or 8 days after A. hydrophila infection, indicating the activation of NF-κB signaling. Correlating with the augmented protein phosphorylation, leukocyte proliferation was enhanced during the same immune stage, suggesting the potential association of IκBα and IκBα-regulated NF-κB signaling in the primary adaptive immune response. Although lymphocyte activation by the T cell-specific mitogen PHA did not alter On-IκBα mRNA expression significantly, lymphocyte activation by the agonist PMA obviously elevated On-IκBα and OnNF-κB p65 phosphorylation in spleen leukocytes. Together, the results suggest that IκBα phosphorylation and its regulated NF-κB activation are essential events associated with lymphocyte activation, proliferation, and anti-bacterial adaptive immune response in Nile tilapia. Our study aids to understand the regulatory mechanism of adaptive immunity in teleost.

  View details for DOI 10.1016/j.dci.2019.103526

  View details for Web of Science ID 000500050700024

  View details for PubMedID 31655126

• Involvement of H-Ras in the adaptive immunity of Nile tilapia by regulating lymphocyte activation FISH & SHELLFISH IMMUNOLOGY Wei, X., Zhao, T., Zhang, Y., Ai, K., Li, H., Yang, J. 2019; 89: 281-289

  Abstract

  H-Ras is a guanosine triphosphatase (GTPase), which acts as a molecular switch and controls multiple important cellular processes including lymphocyte activation and function. However, regulatory mechanism of adaptive immune response by H-Ras remains unclear in non-mammalian animals. In the present study, we investigated the involvement of H-Ras in lymphocyte activation with a teleost model Oreochromis niloticus. H-Ras from O. niloticus (On-H-Ras) is highly conserved with those from other vertebrates. The mRNA of On-H-Ras showed a wide expression pattern in the lymphoid-tissues and with the highest level in liver. After Aeromonas hydrophila infection, transcription of On-H-Ras was significantly induced on day 8 but came back to basal level on day 16, suggesting that On-H-Ras potentially participated in primary response during the adaptive immunity. Furthermore, On-H-Ras mRNA was obviously up-regulated when leukocytes were activated by T lymphocyte mitogen PHA in vitro. Meanwhile, protein level of H-Ras was also augmented once leukocytes were stimulated with lymphocyte receptor signaling agonist PMA and ionomycin. More importantly, once Ras activity was inhibited by specific inhibitor, the up-regulation of lymphocyte activation marker CD122 was obviously impaired during lymphocyte activation process. Therefore, On-H-Ras regulated lymphocyte activation through both mRNA and protein level. Altogether, our results illustrated the involvement of H-Ras in teleost adaptive immunity via controlling lymphocyte activation, and thus provided a novel perspective to understand evolution of the lymphocyte-mediated adaptive immunity.

  View details for DOI 10.1016/j.fsi.2019.04.003

  View details for Web of Science ID 000469897700032

  View details for PubMedID 30953781

• c-Raf participates in adaptive immune response of Nile tilapia via regulating lymphocyte activation FISH & SHELLFISH IMMUNOLOGY Wei, X., Zhao, T., Ai, K., Zhang, Y., Li, H., Yang, J. 2019; 86: 507-515

  Abstract

  RAF proto-oncogene serine/threonine-protein kinase (c-Raf) is a MAP kinase kinase kinase (MAPKKK) that participates in the Erk1/2 pathway and plays an important role in lymphocyte activation. However, the study on how c-Raf regulates adaptive immunity in non-mammal is still limited. In present study, based on analysis of sequence characteristics of c-Raf from Oreochromis niloticus (On-c-Raf), we investigated its regulation roles on teleost lymphocyte activation. The On-c-Raf was highly conserved during evolution, which was composed of a Raf-like Ras-binding domain (RBD), a protein kinase C conserved region 1 (C1) domain and a serine/threonine protein kinase catalytic (S_TKc) domain. Its mRNA showed a wide distribution in tissues of O. niloticus and with the highest expression in gill. After Aeromonas hydrophila infection, during the adaptive immune stage transcription level of On-c-Raf was significantly upregulated on day 8, but came back to original level on day 16 and 30, suggesting the potential involvement of On-c-Raf in primary response but not memory formation. Furthermore, On-c-Raf mRNA in leukocytes of Nile tilapias was obviously induced by in vitro stimulation of T cell mitogen PHA. More importantly, in vitro stimulation of lymphocytes agonist PMA augmented phosphorylation level of On-c-Raf in leukocytes detected by western-blot and immunofluorescent. Thus, c-Raf regulated lymphocyte activation of Nile tilapia on both mRNA and phosphorylation level. Together, our results revealed that the c-Raf from teleost Nile tilapia engaged in adaptive immune response by regulating lymphocytes activation. Since the regulatory mechanism of lymphocyte-mediated adaptive immunity is largely unknown in teleost, our study provided important evidences to understand teleost adaptive immunity, and also shed a novel perspective for the evolution of adaptive immune system.

  View details for DOI 10.1016/j.fsi.2018.11.072

  View details for Web of Science ID 000459528400059

  View details for PubMedID 30513386

• Galactoside-binding lectin in <i>Solen grandis</i> as a pattern recognition receptor mediating opsonization FISH & SHELLFISH IMMUNOLOGY Zhao, T., Wei, X., Yang, J., Wang, S., Zhang, Y. 2018; 82: 183-189

  Abstract

  Galactoside-binding lectin (galectin) is a type of pathogen recognition molecule that occupies an important position in the invertebrate innate immunity system. Our previous study has identified a galectin gene in mollusk Solen grandis (SgGal-1) and illustrated its potential roles in innate immunity. By the functional study using recombinant protein and specific antibody, here, we confirmed the pivotal roles of SgGal-1 in immune defense of S. grandis. SgGal-1 protein was expressed in many tested tissues including gill, mantle, hepatopancreas and gonad, except hemocytes and muscle. The recombinant SgGal-1 (rSgGal-1) bound PGN and β-glucan instead of LPS in vitro, and it further caused significant agglutination of five different microbes, suggesting SgGal-1 served as a pattern recognition receptor (PRR) involved in immune defense of mollusk. Furthermore, SgGal-1 recruited hemocytes to encapsulate, which was blocked by anti-rSgGal-1 serum. In the meantime, rSgGal-1 as well as promoted the phagocytosis of hemocytes against Escherichia coli in vitro. All these results suggested that SgGal-1 in S. grandis not only acted as a PRR recognizing microbes but also directly participated in the process of immune opsonization to protect the host from pathogenic infection.

  View details for DOI 10.1016/j.fsi.2018.08.023

  View details for Web of Science ID 000447571600022

  View details for PubMedID 30107261

• Role of scavenger receptor from <i>Octopus ocellatus</i> as a co-receptor of Toll-like receptor in initiation of TLR-NF-κB signaling during anti-bacterial response DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY Wei, X., Zhao, T., Ai, K., Li, H., Jiang, X., Li, C., Wang, Q., Yang, J., Zhang, R., Yang, J. 2018; 84: 14-27

  Abstract

  Scavenger receptors are crucial for innate immunity owing to their prominent role in clearance of harmful endogenous factors, immune recognition, and more importantly, as co-receptors of Toll-like receptors (TLRs) to initiate downstream responses. At present, invertebrate scavenger receptors, especially their role in immune mechanisms, are largely unknown. We report here that scavenger receptors form a diverse superfamily in Octopus ocellatus, including at least five different members with distinct tissue expression patterns. Two members, OoSR-B and OoSR-I, are grouped into class B and I scavenger receptors, respectively. OoSR-B and OoSR-I are located on the hemocyte membrane, and both recombinant scavenger receptors could serve as pattern recognition receptors to bind a broad range of pathogen-associated molecular patterns. Although OoSR-B and OoSR-I expression was induced by bacterial stimulation, only OoSR-B promoted hemocyte phagocytosis. Moreover, OoSR-B, but not OoSR-I, could act as a co-receptor of TLR to activate TLR-NF-κB signaling and initiate TNF-α production during anti-bacterial response. As the first report on an invertebrate scavenger receptor acting as a co-receptor of TLR, our study reveals the immune mechanism mediated by scavenger receptors in O. ocellatus, and provides new insight into the evolution of this important receptor family.

  View details for DOI 10.1016/j.dci.2018.01.023

  View details for Web of Science ID 000431160800002

  View details for PubMedID 29409792

• Peptidoglycan recognition protein of <i>Solen grandis</i> (SgPGRP-S1) mediates immune recognition and bacteria clearance FISH & SHELLFISH IMMUNOLOGY Wei, X., Yang, D., Li, H., Zhao, T., Jiang, H., Liu, X., Yang, J. 2018; 73: 30-36

  Abstract

  Peptidoglycan recognition proteins (PGRPs) are indispensable molecules in innate immunity due to their prominent function in sensing and eliminating invading microorganisms. In the present study, a short type PGRP from razor clam Solen grandis (SgPGRP-S1) was recombinantly expressed and purified to investigate its potential function in innate immunity. As a pattern recognition receptor, recombinant SgPGRP-S1 (rSgPGRP-S1) specifically bind Lys-type and Dap-type peptidoglycan in vitro, but not lipopolysaccharide or β-glucan. The peptidoglycan binding ability of rSgPGRP-S1 resulted in significant agglutination activity against Gram-negative Escherichia coli and Listonella anguillarum, as well as Gram-positive Micrococcus luteus. Furthermore, rSgPGRP-S1 was bactericidal, significantly suppressing the growth of both E. coli and Gram-positive Staphylococcus aureus. The protein also exhibited strong amidase activity and degraded bacterial peptidoglycan in the presence of Zn2+, suggesting amidase activity might contribute to SgPGRP-S1 antibacterial activity. These results indicate SgPGRP-S1 is multifunctional in innate immunity, mediating both immune recognition and bacteria elimination.

  View details for DOI 10.1016/j.fsi.2017.12.001

  View details for Web of Science ID 000424853100004

  View details for PubMedID 29208495