Thesis
Role of CADM1 in reducing viability of melanoma circulating tumor cells
Master of Science (M.S.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000752
Abstract
Patients diagnosed with metastatic melanoma are faced with few treatment options that frequently result in therapeutic resistance and disease progression. Melanoma circulating tumor cells (CTCs) are particularly dangerous for their ability to reseed at distant organs from primary and metastatic lesions, thus increasing the overall tumor heterogeneity and potentially driving therapeutic resistance. Melanoma metastasis is associated with epithelial-mesenchymal like transitions including changes in expression patterns of cell adhesion molecules. Cell adhesion molecule 1, CADM1 - a single transmembrane protein with three Ig repeats and a short cytosolic tail, is a novel adhesion molecule implicated as a suppressor of metastatic traits in melanoma. Patients with high levels of CADM1 expression have improved overall survival, an effect that may be linked to a CADM1 associated non-adherent cell death - potentially reducing the viability of circulating melanoma tumor cells, and thus limiting tumor reseeding. Preliminary data indicate this phenotype is caspase-independent and exhibits features that parallel parthanatoic cell death: hyperactive poly (ADP)-ribose polymerase 1, PARP1, increased levels of poly-ADP ribose (PAR), and metabolic failure. Here we uncovered further evidence of canonical parthanatos including PARylation of the effector protein AIF. Additionally, through mutational analysis, we found the most distal CADM1 Ig repeat is required for eliciting cell death. Importantly, we also provide preliminary evidence suggesting that poly-ADP ribose glycohydrolyase inhibitors (PARG) - an enzyme involved in recycling PAR chains, thus counter-acting PARP1 activity, can augment CADM1 associated parthanatoic-like cell death. These data provide proof-of-concept for using PARG inhibitors to further stimulate CADM1 linked non-adherent cell death; an effect that may provide clinical benefit by reducing the viability of melanoma CTCs.
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Details
- Title
- Role of CADM1 in reducing viability of melanoma circulating tumor cells
- Creators
- Julia Oleksak
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 50 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991015242079704721