Estrogen receptor (ER)? exhibits an antitumor activity in multiple cancer types in both tumor-intrinsic and -extrinsic manners. However, little is known as to how such activity can be harnessed with high efficacy and precision, nor is it clear which host cell type(s) mediates the tumor-extrinsic function of ER?. These major knowledge gaps hamper efforts to unleash ER? antitumor activity for cancer therapies. We recently discovered a phosphotyrosine-dependent signaling axis that controls ER? antitumor activity. Furthermore, using a novel knockin mouse model, we found that this phosphotyrosine switch plays a significant role in host cells to promote antitumor immunity. Our central hypothesis is that this ER?-centered signaling axis provides a previously unrecognized molecular handle for mobilizing tumor-extrinsic antitumor activity of ER? in immune cells. Armed with genetic and pharmacological tools that both specifically target this signaling circuit, our multi-PI team will validate this novel hypothesis through three Specific Aims. First, we will identify the exact immune cell type(s) that mediates tumor-extrinsic ER? signaling in antitumor immunity (Aim 1). We will then delineate the upstream regulators and downstream target genes of ER? signaling in immune cells (Aim 2). Lastly, we will assess the anticancer therapeutic potential of targeting this ER? signaling axis to boost current cancer immunotherapies. Findings from these experiments will shed light on a previously under-appreciated signaling pathway governing tumor-immune cell interactions in the tumor microenvironment. As immunotherapies are becoming an important pillar of cancer therapy, the proposed study will help improve clinical outcomes and efficacy of immunotherapy for larger numbers of cancer patients.
Our studies will offer exciting insight into a newly discovered phosphotyrosine switch that controls the antitumor ER? functions in host immune cells. In addition, the proposed work will guide the development of ER?-targeting therapeutics in combination with promising immunotherapies. Thus, the novel hypothesis, imminent translational potential, and powerful technical tools promise both conceptual and technical advances in cancer treatment.
|Sun, Xiujie; Gupta, Kshama; Wu, Bogang et al. (2018) Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice. J Biol Chem 293:2841-2849|
|Gupta, Harshita B; Clark, Curtis A; Yuan, Bin et al. (2016) Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 1:|