There is an unmet need to develop novel chemotherapeutics that enhance selectivity and specificity for targeting chemo-resistant tumors. In particular, new strategies that attack chemotherapy-insensitive cancer stem cells/tumor initiating cells (TICs) are lacking. The goal of this proposal is to understand the interplay between TICs and their microenvironment during the transition to invasion and metastasis, as well as to develop a novel treatment reagent to specifically induce invasive TIC death in a preclinical setting. Our central hypothesis is that a cell surface-anchored protease, matrix metalloproteinase-14 (MMP-14), is a key molecule capable of executing the switch in epithelial TICs from quiescent to invasive cells, thereby controlling metastasis. Development of reagents to selectively and specifically target invasive TICs utilizing an MMP-14 binding peptide will facilitate prevention of cancer dissemination. The rationale for this project is that the development of a specific tumor-homing vehicle that carries inhibitory peptide and cytotoxic drug will allow us to not only block cancer invasion but to also induce cancer cell death. Furthermore, this study will advance our understanding of how the microenvironment influences quiescent TICs to give rise to metastases. We plan to test our hypothesis by pursuing the following three specific aims:1) Elucidate the role and mechanism of MMP-14 in conversion of quiescent TICs to invasive cells under hypoxic conditions;2) Define the mechanism of action of an MMP-14 homing peptide;and 3) Develop a bi-functional reagent that specifically targets cancer invasiveness and induces cancer cell death. With respect to the expected outcomes, the work proposed in this application will potentially result in development of a bi-functional reagent capable of delivering a potent chemotherapeutic drug to invasive TICs. This project is innovative because it utilizes novel peptides specific for MMP-14 to selectively target invasive TICs. The proposed research will have significant future implications because it is expected to vertically advance our understanding of how quiescent TICs become reprogrammed into invasive TICs in a hypoxic environment. The developed bi-functional reagent will have a positive impact on future cancer prevention/treatment and could eventually improve the outcome of patients with cancer.
The proposed research will increase our understanding of the reprogramming of cancer from non-metastatic to metastatic. In addition, it will facilitate the development of tools for treatment and prevention of cancer dissemination. Thus, the proposed research is relevant to the NIH's mission that pertains to developing fundamental knowledge that will help to reduce risk of death from various cancers and will improve public health.
|Alford, Vincent M; Kamath, Anushree; Ren, Xiaodong et al. (2017) Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions. ACS Chem Biol 12:2788-2803|
|Cathcart, Jillian M; Banach, Anna; Liu, Alice et al. (2016) Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression. Oncotarget 7:61107-61120|
|Evensen, Nikki A; Li, Yiyi; Kuscu, Cem et al. (2015) Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP). Oncotarget 6:20723-39|
|Li, Yiyi; Kuscu, Cem; Banach, Anna et al. (2015) miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14. Cancer Res 75:2674-85|
|Pulkoski-Gross, Ashleigh; Li, Jian; Zheng, Carolina et al. (2015) Repurposing the antipsychotic trifluoperazine as an antimetastasis agent. Mol Pharmacol 87:501-12|
|Cathcart, Jillian; Pulkoski-Gross, Ashleigh; Cao, Jian (2015) Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. Genes Dis 2:26-34|
|Evensen, Nikki A; Li, Jian; Yang, Jie et al. (2013) Development of a high-throughput three-dimensional invasion assay for anti-cancer drug discovery. PLoS One 8:e82811|
|Evensen, Nikki A; Kuscu, Cem; Nguyen, Hoang-Lan et al. (2013) Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst 105:1402-16|
|Zucker, Stanley; Cao, Jian (2012) New wrinkle between cancer and blood coagulation: metastasis and cleavage of von Willebrand factor by ADAM28. J Natl Cancer Inst 104:887-8|
|Kuscu, Cem; Evensen, Nikki; Kim, Deborah et al. (2012) Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer. PLoS One 7:e44661|
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