Reversing epithelial-mesenchymal transition in metastatic cancer cells using engineered nanomaterials and a mild photothermal effect

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Project Summary Tumor metastasis accounts for 90% of cancer-associated mortality. Epithelial-mesenchymal transition (EMT) of cancer cells provides the cancer cells with strong migratory-invasive abilities, and more recently, to mediate the development of chemoresistance, which is linked to cancer stem cell-like features. There is growing evidence suggesting that targeting EMT can be used as a therapeutic approach itself, or to enhance the efficacy of other anticancer treatments. However, the translation of EMT targeted compounds to the clinic has been challenging due to the lack of molecular-cellular targeting specificity and efficacy. Moreover, most of these compounds only focus on the prevention of EMT, but not on the tumor cells that have already undergone EMT. Innovations that are more specific, effective, and broadly applicable to eliminate EMT-type cancer cells with high metastatic capability and enhanced drug resistance hold great potential to revolutionize the treatment of tumor metastasis. In this project, we will develop a biomaterial-based approach to reverse the EMT of cancer cells by targeting a transmembrane EMT inducer, CD146, using engineered black phosphorus nanosheets (BPNs) and a mild photothermal effect. Our central hypothesis is that CD146 targeted BPNs and a mild hyperthermia will synergistically reverse the EMT in cancer cells, and thus stop the cancer cell migration and sensitize the cancer cells to classical chemotherapy drugs. Our preliminary studies have been able to demonstrate this approach in reversing the EMT of breast cancer cells, leading to nearly stopped cancer cell migration. As CD146 is overexpressed on a series of metastatic cancer cells, we will extend this approach to two other cancer types (including prostate cancer and melanoma), and uncover its working mechanism, which will lay the foundation for the next phase in vivo studies. Three aims have been set to test the hypothesis. Aim 1 will synthesize, optimize, and characterize CD146 targeted BPNs, and evaluate the approach based on CD146 targeted BPNs and a mild hyperthermia for the inhibition of cancer cell migration. Aim 2 will evaluate the efficacy of this approach in reversing the EMT process in cancer cells and the effectiveness of this approach in sensitizing the cancer cells to classical chemotherapeutics. Aim 3 will elucidate the molecule mechanism of how this approach reverses the EMT process in cancer cells. The proposed research is transformative in that (i) it will offer a new perspective for treating cancers by eliminating EMT-type cancer cells and minimizing their invasiveness and chemoresistance; and (ii) the mechanistic knowledge generated by this work will inform the future design of biophotonic nanomaterials to modulate cell phenotypes for in vivo cancer treatment and beyond. This research will also strengthen undergraduate research activities in biomedical engineering at the South Dakota School of Mines and Technology by recruiting nine undergraduate students into the proposed research (three for each year). Students will gain substantial knowledge and skills in biomedical research, which will prepare the students for a successful career in biomedical and health sciences.