Metastasis of cancer cells from the primary site to distant organs is a major cause of cancer-related death, as current chemotherapies are largely ineffective against metastasis. Recent data from the PIs' lab suggest that colorectal cancer (CRC) cells may undergo remarkable metabolic reprogramming after they metastasize to liver, which is the most common site for CRC metastasis. This discovery makes the conceptual argument that altered metabolism may contribute to metastatic phenotypes. The proposed study will use an integrative systems approach to understand metabolic reprogramming of CRC liver metastasis. Primary and liver tumors from an in vivo CRC metastasis model will be profiled by RNA-seq and high-resolution, liquid chromatography-mass spectrometry (LC-MS) based metabolomics. Integrated network analysis of the transcriptome and metabolome will identify altered metabolic pathways in CRC metastases. The findings will be corroborated by an extensive clinical biobank that contains a large collection of CRC liver metastases. Based on the integrative systems analysis, this study will then explore the hypothesis that manipulation of metabolic reprogramming will interfere with growth of CRC liver metastasis. Preliminary data suggest that targeting dysregulated metabolism, which includes inhibition of enzymes and restrictive diets, can interfere with growth of liver metastases more than frontline chemotherapy can in animal models. Since metastatic tumor cells have to adapt to their new microenvironment, targeting metabolic reprogramming of metastasis may be a viable approach for multiple cancer types and a significant percentage of the patient population.

Public Health Relevance

The study will use an integrative systems approach to study how colon cancer cells are metabolically rewired after they metastasize to liver, and test a hypothesis that targeting metabolic reprogramming will interfere with growth of colon cancer liver metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA201963-02
Application #
9205492
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Li, Jerry
Project Start
2016-01-13
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Bu, Pengcheng; Chen, Kai-Yuan; Xiang, Kun et al. (2018) Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. Cell Metab 27:1249-1262.e4
Chen, Kai-Yuan; Srinivasan, Tara; Lin, Christopher et al. (2018) Single-Cell Transcriptomics Reveals Heterogeneity and Drug Response of Human Colorectal Cancer Organoids. Conf Proc IEEE Eng Med Biol Soc 2018:2378-2381
Lu, Min; Sanderson, Sydney M; Zessin, Amelia et al. (2018) Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer. Cancer Metab 6:14
Dai, Ziwei; Locasale, Jason W (2017) Understanding metabolism with flux analysis: From theory to application. Metab Eng 43:94-102
Wang, Xiuxing; Yang, Kailin; Xie, Qi et al. (2017) Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nat Neurosci 20:661-673
Gao, Xia; Reid, Michael A; Kong, Mei et al. (2017) Metabolic interactions with cancer epigenetics. Mol Aspects Med 54:50-57
Mentch, Samantha J; Locasale, Jason W (2016) One-carbon metabolism and epigenetics: understanding the specificity. Ann N Y Acad Sci 1363:91-8
Sadhukhan, Sushabhan; Liu, Xiaojing; Ryu, Dongryeol et al. (2016) Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 113:4320-5
Joe, Daniel J; Hwang, Jeonghyun; Johnson, Christelle et al. (2016) Surface Functionalized Graphene Biosensor on Sapphire for Cancer Cell Detection. J Nanosci Nanotechnol 16:144-51
Ser, Zheng; Gao, Xia; Johnson, Christelle et al. (2016) Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow. Cell Rep 15:2367-76

Showing the most recent 10 out of 11 publications