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Author(s): John P. Morris IV [sup.1] , Jossie J. Yashinskie [sup.2] [sup.3] [sup.4] , Richard Koche [sup.3] , Rohit Chandwani [sup.5] [sup.6] [sup.7] [sup.8] , Sha Tian [sup.1] , Chi-Chao [...], The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC).sup.1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development.sup.2. Wild-type p53 is also known to modulate cellular metabolic pathways.sup.3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of [alpha]-ketoglutarate ([alpha]KG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable [alpha]KG. Increased levels of the [alpha]KG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of [alpha]KG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase--an enzyme of the tricarboxylic acid cycle--specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of [alpha]KG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that [alpha]KG is an effector of p53-mediated tumour suppression, and that the accumulation of [alpha]KG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression. Restoring the function of p53 in a mouse model of pancreatic ductal adenocarcinoma leads to the accumulation of [alpha]-ketoglutarate, which increases levels of the 5-hydroxymethylcytosine chromatin modification and results in reduced tumour-cell fitness.

Introduction Cancer remains a deadly disease since patients often relapse after surgery and adjuvant therapy, progressing to advanced metastatic stages (1). Recent studies have shown that cancer cells, beyond their [...], Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the pulse-chase expression of H2BeGFP for labeling and isolating slow-cycling cancer cells (SCCCs). SCCCs showed cancer initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive nongenetic and cell- autonomous gene expression profile shared across different tumor types. We identified TET2 epigenetic enzyme as a key factor controlling SCCC numbers, survival, and tumor recurrence. 5-Hydroxymethylcytosine (5hmC), generated by TET2 enzymatic activity, labeled the SCCC genome in carcinomas and was a predictive biomarker of relapse and survival in cancer patients. We have shown the enhanced chemoresistance of SCCCs and revealed 5hmC as a biomarker for their clinical identification and TET2 as a potential drug target for SCCC elimination that could extend patients' survival.

Chromosomal instability (CIN) is commonly found in human solid tumours, and extensive studies with mouse models suggest that it is sufficient to initiate tumorigenesis in a variety of cellular contexts [...], Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction (1).This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents. However, there has been no systematic exploration of whether chromosomal instability generated as a result of deregulation of the mitotic checkpoint pathway (2,3),a frequent characteristic of solid tumours, has any effect on oncogene addiction. Here we show that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 in mice does not affect the regression of Kras-driven lung tumours when Kras is inhibited. However, tumours that experience transient Mad2 overexpression and consequent chromosome instability recur at markedly elevated rates. The recurrent tumours are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early chromosomal instability may be responsible for tumour relapse after seemingly effective anticancer treatments.