Glutamine addiction promotes glucose oxidation in triple-negative breast cancer

Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies

ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes

Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma

De Verenigde Staten van Midden-Amerika? De lezingen

In de maanden februari/maart 1988 organiseerde Bureau Studium Generale een lezingen- en discussie-programma over Midden-Amerika. Een van de centrale vragen in dit programma was die naar de eigen Midden-amerikaanse identiteit. In de lezingen, waarvan deze bundel verslag doet, is vanuit vele invalshoeken op Midden-Amerika ingegaan. De betrokkenheid waarmee dit gebeurde, maakte het programma tot een bijzondere gebeurtenis. Een tweetal lezingen ontbreken helaas: Een verslag van de avond "Nederland en Midden-Amerika", waarop na een bijdrage van mr. J.J.A.M. van Gennip (min. van ontwikkelingssamenwerking) een forum-discussie werd gevoerd door Ferry Franssen (journalist), Gemma den Hooff (Guatemala Komitee) en Pieter van Veenen (Humanistisch Overleg Mensenrechten). Ook de lezing op de laatste avond in het programma, van drs. K. Wellinga, ontbreekt helaas. T.a.v. de bijdrage van prof.dr. E.W.K. FitzGerald, wordt hier opgemerkt dat wij zijn lezing van cassette op papier hebben gezet. Hij heeft daarna geen mogelijkheden meer gehad om het verhaal te bewerken. Spreektaal is wat anders dan schrijftaal. Dat is in het stuk te merken. Toch hebben wij gemeend er goed aan te doen het stuk op te nemen. Het was een inspirerende avond

De Verenigde Staten van Midden-Amerika? De lezingen

In de maanden februari/maart 1988 organiseerde Bureau Studium Generale een lezingen- en discussie-programma over Midden-Amerika. Een van de centrale vragen in dit programma was die naar de eigen Midden-amerikaanse identiteit. In de lezingen, waarvan deze bundel verslag doet, is vanuit vele invalshoeken op Midden-Amerika ingegaan. De betrokkenheid waarmee dit gebeurde, maakte het programma tot een bijzondere gebeurtenis. Een tweetal lezingen ontbreken helaas: Een verslag van de avond "Nederland en Midden-Amerika", waarop na een bijdrage van mr. J.J.A.M. van Gennip (min. van ontwikkelingssamenwerking) een forum-discussie werd gevoerd door Ferry Franssen (journalist), Gemma den Hooff (Guatemala Komitee) en Pieter van Veenen (Humanistisch Overleg Mensenrechten). Ook de lezing op de laatste avond in het programma, van drs. K. Wellinga, ontbreekt helaas. T.a.v. de bijdrage van prof.dr. E.W.K. FitzGerald, wordt hier opgemerkt dat wij zijn lezing van cassette op papier hebben gezet. Hij heeft daarna geen mogelijkheden meer gehad om het verhaal te bewerken. Spreektaal is wat anders dan schrijftaal. Dat is in het stuk te merken. Toch hebben wij gemeend er goed aan te doen het stuk op te nemen. Het was een inspirerende avond

Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment

International audienc

Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth

Glutamine is a critical nutrient in cancer; however, its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. We utilized [15N-(amide)]glutamine and [U-13C5]glutamine metabolomics to dissect the pathways involved and despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown, highlighting the importance of glutamine metabolism and providing support for GMPS as a therapeutic target in prostate cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd