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Principal Investigator: Steve J Smith
Organization: SOUTH DAKOTA SCHOOL OF MINES AND TECHN'Y
Fiscal Year: 2022
Award: $413,479
Funding agency: National Cancer Institute
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.
Terms: <3-D><3-Dimensional><3D><Abscission><Actins><Anti-Cancer Agents><Antibodies><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Assay><Atomic Force Microscopy><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biocompatible Materials><Biologic Assays><Biological Assay><Biomaterials><Biomedical Engineering><Biomedical Research><Biophotonics><Breast><Breast Cancer Cell><CD146><Cadherin-1><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cell Line><Cell Locomotion><Cell Migration><Cell Movement><CellLine><Cells><Cellular Matrix><Cellular Migration><Cellular Morphology><Cellular Motility><Characteristics><Chemoresistance><Chicken Homolog of Gicerin><Clinic><Co(beta)-cyano-7''-(2-methyl)adeninylcobamide><Complement><Complement Proteins><Cytokeratin><Cytoplasm><Cytoskeletal System><Cytoskeleton><Development><Disseminated Malignant Neoplasm><Dissociation><Dose><Drug resistance><Drugs><E-Cadherin><Effectiveness><Engineering><Ensure><Epithelial><Epithelial Calcium-Dependent Adhesion Protein><Epithelial-Cadherin><Event><Excision><Extirpation><Fluorescence Light Microscopy><Fluorescence Microscopy><Force Microscopy><Foundations><Future><GTP><General Transcription Factor Gene><General Transcription Factors><Generations><Guanine Nucleotides><Guanosine Phosphates><Guanosine Triphosphate><Health Sciences><Hyperthermia><Immunoblotting><Interruption><Knowledge><Laser Electromagnetic><Laser Radiation><Lasers><Link><Lytotoxicity><MCAM><MCAM gene><MUC18><Malignant Cell><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Melanoma Adhesion Molecule><Melanoma Cell><Melanoma-Associated Glycoprotein MUC18><Membrane><Mesenchymal><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Prostate Cancer><Metastatic Tumor><Modeling><Molecular><Motility><N-Cadherin><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Normal Cell><Operative Procedures><Operative Surgical Procedures><Ovary Cancer><P element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phenotype><Phosphorous><Phosphorus><Phosphorylation><Play><Prevention><Process><Prostate><Prostate CA><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate Gland><Prostatic Cancer><Prostatic Gland><Protein Phosphorylation><Pulmonary Cancer><Pulmonary malignant Neoplasm><Removal><Research><Research Activity><Resolution><Role><Scanning Force Microscopy><Schools><Secondary Neoplasm><Secondary Tumor><Series><South Dakota><Specificity><Strains Cell Lines><Students><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Technology><Testing><Therapeutic><Transcription Factor Proto-Oncogene><Transcription factor genes><Translations><Tumor Cell><Tumor-Specific Treatment Agents><Up-Regulation><Upregulation><Uvomorulin><Vimentin><Western Blotting><Western Immunoblotting><Work><Wound Repair><anti-cancer drug><anti-cancer therapy><anti-cancer treatment><anticancer agent><anticancer drug><anticancer therapy><anticancer treatment><assess effectiveness><base><bio-engineered><bio-engineers><bioengineering><biological engineering><biological material><breast tumor cell><cancer cell><cancer metastasis><cancer progenitor cells><cancer progression><cancer stem cell><cancer therapy><cancer type><cancer-directed therapy><career><cell morphology><cell motility><cell type><cellular targeting><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><cultured cell line><cytotoxicity><density><design><designing><determine effectiveness><developmental><drug resistant><drug/agent><effectiveness assessment><effectiveness evaluation><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><evaluate effectiveness><evaluate efficacy><examine efficacy><ezrin><factor A><in vivo><innovate><innovation><innovative><intracellular skeleton><lung cancer><malignancy><malignant stem cell><melanoma><membrane structure><membrane-organizing extension spike protein><migration><moesin><mortality><nano materials><nano mechanics><nanomaterials><nanomechanics><nanosheet><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><ovarian cancer><overexpress><overexpression><phosphoprotein p81><prevent><preventing><prostate cancer cell><prostate tumor cell><protein blotting><radixin><radixin protein><recruit><resection><resistance to Drug><resistant to Drug><rho><skills><social role><stem-like cell><surgery><three dimensional><transcription factor><tumor><tumor cell metastasis><tumor progression><undergrad><undergraduate><undergraduate research><undergraduate student><uptake><wound healing><wound resolution>