Abstract
Asparagine depletion reduces breast cancer invasion and metastasis without affecting primary tumor growth.
Major finding: Asparagine depletion reduces breast cancer invasion and metastasis without affecting primary tumor growth.
Mechanism: Asparagine content is selectively elevated in proteins that drive epithelial-to-mesenchymal transition.
Impact: Therapies that alter asparagine levels may potentially inhibit breast cancer metastasis.
Metastatic relapse is the main cause of mortality in patients with breast cancer; recently, it has been shown that clonal subpopulations of primary mouse mammary 4T1 tumors that are equally proficient at generating circulating tumor cells (CTC) exhibited variable metastatic potential. To identify drivers of breast cancer metastasis, Knott, Wagenblast, and colleagues performed gene expression analysis of two CTC-proficient 4T1 subclones, the highly metastatic subclone 4T1-T and the nonmetastatic subclone 4T1-E. Candidate drivers, which were overexpressed in 4T1-T cells compared with 4T1-E cells, were enriched for metastasis-associated genes and overexpressed in primary breast tumors that subsequently exhibited relapse of disseminated breast cancer. In vitro and in vivo screening of 4T1-T cells with candidate drivers targeted by pools of shRNAs identified asparagine synthetase (Asns) as the most clinically relevant candidate driver of breast cancer metastasis. Although Asns depletion in 4T1-T cells did not affect primary tumor growth in vivo, Asns-depleted 4T1-T cells had decreased invasive potential in vitro and metastatic potential in vivo. Metastases were nearly undetectable after treatment with L-asparaginase, which degrades asparagine, in ASNS-silenced 4T1 or MDA-MB-231 orthotopic tumor models, although in these models primary tumor growth was also suppressed. Similarly, parental 4T1 cells grown in medium supplemented with asparagine, but not other nonessential amino acids, exhibited increased invasive potential in vitro, and mice harboring 4T1 tumors treated with L-asparaginase or fed a low-asparagine diet experienced a decrease in metastasis with no effect on primary tumor growth. Asparagine silencing resulted in the depletion of proteins associated with epithelial-to-mesenchymal transition (EMT), and proteomic analysis revealed that EMT-associated proteins had higher asparagine content compared with the proteome as a whole. Similarly, Asns-depleted 4T1-T tumors and metastases exhibited decreased expression of EMT markers. These results describe a role for asparagine bioavailability as a driver of metastasis in breast cancer and suggest potential antimetastatic therapeutic approaches.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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