Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells

Abstract

Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translational modification, flux analysis is necessary to conclusively establish phenotypes. In this study, the metabolic phenotypes of breast cancer cell lines with low (T47D) or high (MDA-MB-231) metastatic potential, as well as lung (LM)- and bone (BoM)-homing lines derived from MDA-MB-231 cells, were assessed by 13C metabolite labeling from [1,2-13C] glucose or [5-13C] glutamine and the rates of nutrient and oxygen consumption and lactate production. MDA-MB-231 and T47D cells produced 55 and 63%, respectively, of ATP from oxidative phosphorylation, whereas LM and BoM cells were more glycolytic, deriving only 20–25% of their ATP from mitochondria. ATP demand by BoM and LM cells was approximately half the rate of the parent cells. Of the anabolic fluxes assessed, nucleotide synthesis was the major ATP consumer for all cell lines. Glycolytic NADH production by LM cells exceeded the rate at which it could be oxidized by mitochondria, suggesting that the malate-aspartate shuttle was not involved in re-oxidation of these reducing equivalents. Serine synthesis was undetectable in MDA-MB-231 cells, whereas 3–5% of glucose was shunted to serine by LM and BoM lines. Proliferation rates of T47D, BoM, and LM lines tightly correlated with their respiration-normalized NADPH production rates. In contrast, MDA-MB-231 cells produced NADPH and GSH at higher rates, suggesting this line is more oxidatively stressed. Approximately half to two-thirds of NADPH produced by T47D, MDA-MB-231, and BoM cells was from the oxidative PPP, whereas the majority in LM cells was from the folate cycle. All four cell lines used the non-oxidative PPP to produce pentose phosphates, although this was most prominent for LM cells. Taken together, the metabolic phenotypes of LM and BoM lines differed from the parent line and from each other, supporting the metabolic re-wiring hypothesis as a feature of metastasis to lung and bone.

Metastatic cells exploit their stoichiometric niche in the network of cancer ecosystems

“…Successful colonization emerges from the compatibility of the metastatic cell’s niche and the acceptor’s microenvironmental conditions ( 38 ). To test the P-driven metastatic colonization hypothesis, we reason that a higher likelihood of colonization would be possible in organs with resources to support higher energy production based on the metastatic cell’s requirements needed to fulfil the demands of a fast proliferative strategy ( 17 , 18 , 39 , 40 ). The P content is a measure of phosphate-rich molecules, such as high-energy molecules (ATP), membrane phospholipids, signaling pathways, and RNA/DNA phosphodiester backbones ( 21 , 22 ), and it could give clues about an organ’s conditions to support a demanding metabolism.…”

“…A legacy effect, however, seems to be in action such that the priming of the stoichiometric niche of the pioneer migrant diaspora acquired in the source tissue affects its future success of invading a secondary organ ( 16 ), such as has been suggested for lung cancer ( 17 ) and shown for metastatic breast cancer ( 39 , 40 ). This is analogous to a maternal effect, as known in evolutionary ecology, whereby there is a causal influence of the maternal genotype or phenotype (i.e., the primary organ) on the offspring phenotype (i.e., the primary tumor and its metastatic propagules).…”

The Influence of the Amino Acid Transporter LAT1 on Patient Prognosis and the Relationships between Tumor Immunometabolic and Proliferative Features Depend on Menopausal Status in Breast Cancer

“…Increasing interest in the relationship between systemic metabolism, tumor metabolism, immunometabolism, and cancer outcomes, alongside evolving technologies expanding both the available data and the community's ability to mine it to develop new insights. To that end, in this study, we utilized multiple publicly available breast cancer datasets, including "ACRIN-FLT-Breast (ACRIN 6688)", TCGA BRCA "Phenotypes", TCGA BRCA "IlluminaHiSeq", "TCGA TARGET GTEx", "Node-negative breast cancer (Desmedt 2007)", "ICGC (donor centric)", As opposed to genes or metabolic fluxes involved in glucose [24][25][26][27][28][29][30][31]or lipid metabolism [31][32][33][34][35][36][37][38][39], there exists a relative paucity of studies exploring the impact of expression of genes regulating amino acid uptake in breast cancer. Therefore, we elected to focus the current study on the expression of LAT1, which transports large amino acids including leucine, isoleucine, valine, phenylalanine, methionine, tyrosine, histidine, and tryptophan into the cell, and its relationships with body weight, tumor cell proliferation, and immune infiltration.…”

The association between the amino acid transporter LAT1, tumor immunometabolic and proliferative features and menopausal status in breast cancer

“…As opposed to genes or metabolic fluxes involved in glucose [24][25][26][27][28][29][30][31] or lipid metabolism [31][32][33][34][35][36][37][38][39], there exists a relative paucity of studies exploring the impact of expression of genes regulating amino acid uptake in breast cancer. Therefore, we elected to focus the current study on the expression of LAT1, which transports large amino acids including leucine, isoleucine, valine, phenylalanine, methionine, tyrosine, histidine, and tryptophan into the cell, and its relationships with body weight, tumor cell proliferation, and immune infiltration.…”