Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer characterized by complex metabolic adaptations that promote survival in a severely hypoxic and nutrient-limited tumor microenvironment (TME). Modeling microenvironmental influences in cell culture has been challenging, and technical limitations have hampered the comprehensive study of tumor-specific metabolism in vivo. To systematically interrogate metabolic vulnerabilities in PDA, we employed parallel CRISPR-Cas9 screens using in vivo and in vitro systems. This work revealed striking overlap of in vivo metabolic dependencies with those in vitro. Moreover, we identified that intercellular nutrient sharing can mask dependencies in pooled screens, highlighting a limitation of this approach to study tumor metabolism. Furthermore, metabolic dependencies were similar between 2D and 3D culture, although 3D culture may better model vulnerabilities that influence certain oncogenic signaling pathways. Lastly, our work demonstrates the power of genetic screening approaches to define in vivo metabolic dependencies and pathways that may have therapeutic utility.
['Biancur|Douglas E|DE|', 'Kapner|Kevin S|KS|', 'Yamamoto|Keisuke|K|', 'Banh|Robert S|RS|', 'Neggers|Jasper E|JE|', 'Sohn|Albert S W|ASW|', 'Wu|Warren|W|', 'Manguso|Robert T|RT|', 'Brown|Adam|A|', 'Root|David E|DE|', 'Aguirre|Andrew J|AJ|', 'Kimmelman|Alec C|AC|']
D000818:Animals D064113:CRISPR-Cas Systems D021441:Carcinoma, Pancreatic Ductal D049109:Cell Proliferation D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D009374:Neoplasms, Experimental D010190:Pancreatic Neoplasms D014407:Tumor Cells, Cultured D059016:Tumor Microenvironment
metabolism pancreatic cancer tumor microenvironment cancer cell signaling nutrient crosstalk