Asparagine bioavailability governs metastasis in a model of breast cancer

Abstract

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

“…Recently, the bioavailability of asparagine was reported to govern breast cancer metastasis, and ASNase could reduce breast cancer metastasis (Knott et al , ). From our results above, SLC1A3‐mediated aspartate/glutamate imports could affect ASNase treatment.…”

“…Ye et al () have demonstrated the importance of asparagine synthesis via GCN2‐ATF4 axis for tumor cell survival during nutrient deprivation. And it has been demonstrated the essential role of asparagine in promoting cancer cell proliferation and breast cancer metastasis (Krall et al , ; Knott et al , ; Pavlova et al , ). Our study provides another support for the role of asparagine in cancer biology and puts forward the potential usage of ASNase in cancer therapy.…”

“…It indicates that SLC1A3‐mediated fueling of endogenous aspartate/glutamate levels is a novel contributor to ASNase resistance. Moreover, aspartate was the second most enriched amino acid (after asparagine) for genes related to epithelial‐to‐mesenchymal transition (Knott et al , ). In line with this, we observed that SLC1A3 expression could promote cancer cell metastasis, regardless of asparagine bioavailability (Figs D and EV5E).…”

Locally Trapping the C‐C Chemokine Receptor Type 7 by Gene Delivery Nanoparticle Inhibits Lymphatic Metastasis Prior to Tumor Resection

“…Reports have shown that surgical trauma promoted CTCs implantation and growth, and accordingly accelerated tumor metastasis. In the clinic, most women with breast cancer do not die from primary tumor, but instead from the metastasis after resection . Since metastasis after resection is the leading cause of mortality for TNBC, a preventive therapy prior to tumor resection is urgently needed …”

Conformational Analyses of Physiological Binary and Ternary Copper(II) Complexes with l‐Asparagine and l‐Histidine; Study of Tridentate Binding of Copper(II) in Aqueous Solution

“…Intracellular l ‐Asn levels are suggested to regulate amino‐acid uptake in cells, especially of l ‐Ser, l ‐arginine and l ‐His . Besides, l ‐Asn is considered an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation …”