Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumor suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer(NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behavior. Here we show that human KL cells and tumors share metabolic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumor growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.
Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras (G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras (G12D) expression. Transcriptome and metabolomic analyses indicate that Kras (G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras (G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.
In collaboration with the Society for Hematopathology and the European Association for Haematopathology, the World Health Organization (WHO) published the third and fourth editions of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , in 2001 and 2008, respectively, as part of a series of WHO Classification of Tumours “blue book” monographs. In the spring of 2014, a clinical advisory committee (CAC) composed of ∼100 pathologists, hematologists, oncologists, and geneticists from around the world convened to propose revisions to the fourth edition of the classification. The revision of the fourth edition follows the philosophy of the third and fourth editions to incorporate clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics to define disease entities of clinical significance. The fourth edition of the classification of hematopoietic and lymphoid tissues was the second volume of the WHO “blue book” tumor series, and the series publication is still in progress. A fifth edition series cannot begin until the fourth edition series is completed; but after 8 years of information and experience that have emerged from scientific and clinical studies, a revision of these criteria for hematopoietic and lymphoid neoplasms was felt to be necessary and timely. In relation to myeloid neoplasms and acute leukemia, this revision has been influenced by several factors including the following: