A major premise of this proposal is that RNAs present in biofluids represent a window into various cellular processes that exist in multiple tissues that release such RNAs. We have found that oncogenic KRAS mutations that occur in colorectal cancer can regulate miRNAs, mRNAs and long RNAs secreted from tumor cells in exosomes. This project (project 1) will determine what the mechanisms are by which these RNAs (cRNAs) enter the bloodstream using in vivo models and how these RNAs change with oncogenic mutations. This project will result in the creation of new tools to visualize and analyze such RNAs in real time and from blood samples in mouse models. We propose the following aims to address these questions.
We have found that mutations that are associated with the progression of colon cancer leads to changes in RNAs secreted from cells packaged inside vesicles called exosomes that can travel into the bloodstream. We will perform experiments in living organisms and create tools to assay for and visualize these RNAs and understand how these RNAs get into the blood. This will create new tests for presence and treatment of colon cancer.
|Zhang, Qin; Jeppesen, Dennis K; Higginbotham, James N et al. (2018) Mutant KRAS Exosomes Alter the Metabolic State of Recipient Colonic Epithelial Cells. Cell Mol Gastroenterol Hepatol 5:627-629.e6|
|Hinger, Scott A; Cha, Diana J; Franklin, Jeffrey L et al. (2018) Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells. Cell Rep 25:715-725.e4|
|Sung, Bong Hwan; Weaver, Alissa M (2018) Directed migration: Cells navigate by extracellular vesicles. J Cell Biol 217:2613-2614|
|Maas, Sybren L N; Breakefield, Xandra O; Weaver, Alissa M (2017) Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol 27:172-188|
|McKenzie, Andrew J; Hoshino, Daisuke; Hong, Nan Hyung et al. (2016) KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes. Cell Rep 15:978-987|
|Higginbotham, James N; Zhang, Qin; Jeppesen, Dennis K et al. (2016) Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles 5:29254|
|Dou, Yongchao; Cha, Diana J; Franklin, Jeffrey L et al. (2016) Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci Rep 6:37982|
|Patton, James G; Franklin, Jeffrey L; Weaver, Alissa M et al. (2015) Biogenesis, delivery, and function of extracellular RNA. J Extracell Vesicles 4:27494|
|Quesenberry, Peter J; Aliotta, Jason; Camussi, Giovanni et al. (2015) Potential functional applications of extracellular vesicles: a report by the NIH Common Fund Extracellular RNA Communication Consortium. J Extracell Vesicles 4:27575|
|Cha, Diana J; Franklin, Jeffrey L; Dou, Yongchao et al. (2015) KRAS-dependent sorting of miRNA to exosomes. Elife 4:e07197|
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