Production of inflammatory cytokines and interferons by innate immune cells, within the tumormicroenvironment, is a major determinant of tumor progression. Damage-associated molecular pattern(DAMP) recognizing receptors in myeloid cells are activated by ligands generated by the tumor cells, cytokinesare induced locally and act upon the tumor cells to promote or impair their proliferation. Recent literaturesuggests that DNA and RNA are the major mediators of communication between the tumor cells and the innateimmune cells. Our interests are in analyzing the biochemical pathways of signaling elicited by specific nucleicacid receptors in myeloid cells and investigating the effects of their manipulations in mouse models, which willbe greatly facilitated by the newly generated TLR3, TLR9 and EGFR conditional knock-out mouse lines. Wewill test the hypothesis that the protein tyrosine kinase (PTK) activity of the epidermal growth factor receptor(EGFR) is essential for signaling by the two endosomal Toll-like receptors, TLR3 and TLR9, and by STING, theER-bound mediator of cytoplasmic DNA signaling. Specifically, we will investigate the roles of EGFR and Src inTLR3 and TLR9 signaling by determining the biochemical requirements for TLR, EGFR and Src interactions toelicit signals. We will also identify the specific functions of EGFR and the adaptor protein, TRIF, in mediatingSTING-signaling and their contributions to STING-mediated protection from viral pathogenesis in mice will beevaluated. Finally, we will evaluate the role of EGFR-mediated cytokine production by myeloid cells inregulating tumor growth in three murine model systems: chemically induced skin and colon cancers andtransplanted glioma. The above studies will illuminate the different mechanisms by which EGFR promotessignaling by three intracellular nucleic acid DAMP- recognizing receptors and thereby affects tumor growth.

Public Health Relevance

Because inflammation and cancer progression are closely connected; it is important to understand howimmune cells present in the tumor microenvironment impact the disease process. This proposal is focused ondetermining the role of the epidermal growth factor receptor; a protein tyrosine kinase; in regulating thefunctions of three intracellular pattern recognition receptors that recognize nucleic acids released from dead ordamaged cancer cells. We will examine the effects on tumor progression in mice in which these receptors arenon-functional only in the immune cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Domestic Higher Education
United States
Zip Code
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Veleeparambil, Manoj; Poddar, Darshana; Abdulkhalek, Samar et al. (2018) Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal. J Immunol 200:2809-2818
Nan, Jing; Wang, Yuxin; Yang, Jinbo et al. (2018) IRF9 and unphosphorylated STAT2 cooperate with NF-?B to drive IL6 expression. Proc Natl Acad Sci U S A 115:3906-3911
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Cai, Gang; Zhu, Liang; Chen, Xing et al. (2018) TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A 115:11531-11536
Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:
Wang, Chenhui; Zhang, Cun-Jin; Martin, Bradley N et al. (2017) IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nat Commun 8:15508
Wang, Yuxin; Nan, Jing; Willard, Belinda et al. (2017) Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387. EMBO J 36:202-212
Doherty, Mary R; Cheon, HyeonJoo; Junk, Damian J et al. (2017) Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci U S A 114:13792-13797
Liu, Caini; Zhu, Liang; Fukuda, Koichi et al. (2017) The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo. Sci Signal 10:

Showing the most recent 10 out of 253 publications