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Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis

Publication ,  Conference
Shen, X
Published in: Cancer Research
July 1, 2018

Primary tumors gradually accumulate genetic alterations and are influenced by their microenvironment until they acquire the ability to metastasize to distant organs. Typical of this process, colorectal cancer (CRC) progresses through an adenoma-to-carcinoma sequence that eventually leads to metastasis, preferentially (~70% patients) to the liver. At this phase, the disease becomes challenging to treat and eventually develops resistance to most forms of combination therapy, making CRC metastasis a leading cause of cancer-related deaths. Patients with inoperable liver metastasis respond poorly to chemotherapeutic intervention and have a median survival of 6 to 9 months. Liver lesions have also been shown to seed tertiary tumors in the lungs of patients. Current chemotherapy for advanced CRC does not target liver metastases specifically. This is partly based on observations that CRC metastases are not consistently associated with any specific genetic mutations and they generally resemble cells in the primary tumor. However, emerging evidence suggests that nongenetic alterations, such as epigenetic and metabolic reprogramming, may promote cancer metastasis, including CRC. Targeting such mechanisms may provide a way to enhance therapeutics against metastasis.In this study, pair-wise analysis of 90 matched samples (normal colon, primary CRC, liver metastasis) from 30 Stage IV CRC patients and an in vivo CRC metastasis model via cecum transplantation suggests that CRC liver metastases alter activity levels of certain metabolic pathways. LC-MS based metabolomics systematically mapped the altered metabolic pathways in CRC liver metastasis. In particular, via hypoxia-responsive GATA6 and fructose-responsive ChREBP, liver metastases upregulate ALDOB, an enzyme involved in fructose metabolism, given that 70% of fructose is metabolized in the liver. Intrahepatic implantation indicates that the liver environment causes CRC cells to upregulate ALDOB. Metabolomics and 13C-labeled fructose tracing studies indicate that ALDOB promotes fructose metabolism to fuel glycolysis, gluconeogenesis and the pentose phosphate pathway. Fructose also triggered downstream signaling to enhance lipid synthesis. ALDOB silencing or dietary fructose restriction suppresses growth of CRC liver metastases, but not primary tumors or lung metastases, highlighting the importance of tumor environment. Our findings suggest that metastatic cells can take advantage of abundant metabolites in their new microenvironment, and manipulation of involved pathways impacts the course of metastatic growth.Citation Format: Xiling Shen. Targeting fructose-induced metabolic reprogramming in liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5479.

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

July 1, 2018

Volume

78

Issue

13_Supplement

Start / End Page

5479 / 5479

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Shen, X. (2018). Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis. In Cancer Research (Vol. 78, pp. 5479–5479). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2018-5479
Shen, Xiling. “Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis.” In Cancer Research, 78:5479–5479. American Association for Cancer Research (AACR), 2018. https://doi.org/10.1158/1538-7445.am2018-5479.
Shen X. Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis. In: Cancer Research. American Association for Cancer Research (AACR); 2018. p. 5479–5479.
Shen, Xiling. “Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis.” Cancer Research, vol. 78, no. 13_Supplement, American Association for Cancer Research (AACR), 2018, pp. 5479–5479. Crossref, doi:10.1158/1538-7445.am2018-5479.
Shen X. Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis. Cancer Research. American Association for Cancer Research (AACR); 2018. p. 5479–5479.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

July 1, 2018

Volume

78

Issue

13_Supplement

Start / End Page

5479 / 5479

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis