Exosomal Contents Guided Amino Acids Treatment for Pancreatic Cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT With a 5-year survival rate of less than 5%, Pancreatic adenocarcinoma (PDAC) is a lethal condition with poor outcomes and an increasing incidence. Surgical resection is the only treatment that offers a potential cure, but was limited to the early stage cases without distant metastasis. Currently, there are scarce effective treatments for advanced disease. Chemoradiation and systemic chemotherapy are the mainstay of treatment to slow disease progression at advanced stages. But these therapies cause various side effects, which is one major barrier to the efficacy of anti-tumor therapeutics. There are no known medications that can selectively protect normal tissues from these side effects, and thus an urgent need for novel treatment selectively targeting only tumor cells to improve patient outcomes. Exosomes secreted by tumor cells actively participate in tumor progression and metastasis and contain multiple biomolecules reflecting the status of their parental tumor cells. Investigation of the exosomal contents may lead to a therapeutic inspiration for cancer. We conducted comparative proteomics studies over the malignant and nonmalignant cells at both the cellular and exosomal level. Significant different proteome sets have been identified between the malignant and nonmalignant cells at all levels. Since amino acids are the formation unit of the protein primary sequence, we furthered the proteomics results by studying the distribution of the amino acids statistically between the malignant and nonmalignant cells at both cellular and exosomal level. We found a significant imbalanced amino acid distribution between the tumor cells and exosomes, which is not found between nonmalignant cells and exosomes. This indicates that tumor cells selectively flux certain amino acids out of cells through exosomes, which inspired us to use these amino acids as stressors to tumor cells. The cell viability of the tumor cells treated by these amino acids was significantly decreased, but not that of nonmalignant cells. This exosome-guided observation potentiates a new therapeutic intervention selectively targeting tumor cells. In order to develop the finding into a therapeutic choice for pancreatic cancer, we propose to preclinically validate the treatment in vivo and study the mechanism in vitro.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is a recalcitrant disease for which new therapeutic approaches are desired. We found a therapeutic hint from exosomal analysis and validated it in vitro. In order to develop the finding into a therapeutic choice for pancreatic cancer, we propose to validate the treatment preclinically and study the mechanism.