Chronic and unrelenting inflammation contributes unequivocally to oncogenesis. However, there are many
fundamental challenges in the field of onco-inflammation. Among them, systematic study has not been done to
quantitatively and qualitatively identify and characterize the type of inflammations that is particularly oncogenic.
We hypothesize that oncogenic inflammation is genotoxic and modulated by key innate immune receptors
such as Toll-like receptors (TLRs) in a cell type-specific fashion (Hypothesis 1). In addition, despite the
extensive study of the cancer genome, fewer studies have addressed the roles of protein quality control in
inflammation and oncogenesis. Cancer cells, as compared to normal cells, have a high metabolic demand
which increases the need for protein chaperones that accelerate protein folding. We thus propose that there is
a cancer-specific HSP-client network that plays pivotal roles in inflammation and cancer (Hypothesis 2).
Molecular chaperone gp96 is a paralogue of HSP90 in the endoplasmic reticulum. It is uniformly expressed at
a high level in human cancers, and the high expression of gp96 correlates with worse prognosis. Intriguingly,
we discovered that gp96 is an obligated master chaperone for TLRs. We further revealed that deletion of gp96
in Mfs protect mice against colitis-associated colon cancer, which correlates with a reduced cytokine level and
protection against mutation of Ctnnb1 encoding ß-catenin. We have also generated cell type-specific gp96 KO
mice by deleting gp96 in B cells, regulatory T cells, gut epithelial cells, platelets and dendritic cells. These
unique models allow us to quantify the extent of contribution by these immune cell subsets to inflammation-
associated cancer. In addition, we have shown that gp96 plays essential roles in chaperoning several other
strategically important clients in oncogenesis, including integrins, Wnt co-receptor, Her2, IGF-1 and surface
TGFß docking receptor LRRC32 (GARP). Our findings suggest that gp96 drives oncogenesis by integrating
cell-intrinsic oncogenic client network with inflammation (Hypothesis 3). We will address our hypotheses by first
determining if oncogenic inflammation is modulated by the TLR master chaperone gp96 in a cell type-specific
fashion, using a battery of unique genetic tools. We will then complete the high resolution mapping of cancer-
specific gp96-client network via genetic, pharmacological and biochemical means.
The ultimate goal of this US-China joint project (RFA-AI-16-006) is to uncover both cancer-intrinsic and cancer-
extrinsic roles of gp96 in oncogenesis to guide the development of novel cancer therapeutics in the future.