Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

Distinct epithelial-to-mesenchymal transitions induced by PIK3CAH1047R and PIK3CB.

The most common PIK3CA mutation, producing the H1047R mutant of p110α, arises in myriad malignancies and is typically observed in low-grade breast tumours. In contrast, amplification is observed for wild-type PIK3CB, encoding p110ß, and occurs at low frequency but in aggressive, high-grade metastatic tumours. We hypothesized that mutant p110αH1047R and wild-type p110ß give rise to distinct transformed phenotypes. We show that p110αH1047R and wild-type p110ß, but not wild-type p110α, transform MCF-10A cells and constitutively stimulate phosphoinositide 3-kinase (PI3K)-AKT pathway signalling. However, their resultant morphological transformed phenotypes are distinct. p110αH1047R induced an epithelial-to-mesenchymal transition (EMT) commensurate with SNAIL (also known as SNAI1) induction and loss of E-cadherin. Upon p110ß expression, however, E-cadherin expression was maintained despite cells readily delaminating from epithelial sheets. Distinct from the prominent filopodia in p110αH1047R-expressing cells, p110ß induced formation of lamellipodia, and these cells migrated with significantly greater velocity and decreased directionality. p110ß-induced phenotypic alterations were accompanied by hyperactivation of RAC1; the dependency of transformation of p110ß-binding to Rac1 revealed using a Rac1-binding mutant of p110ß. Thus, PIK3CB amplification induces a transformed phenotype that is dependent upon a p110ß-Rac1 signalling loop and is distinct from the transformed phenotype induced by p110αH1047R.