SUMMARY The altered metabolism of tumors has been considered a target for anti-cancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that over-express MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.

Recent evidence demonstrates that senescence acts as a barrier to tumorigenesis in response to oncogene activation. Using a mouse model of breast cancer, we tested the importance of the senescence response in solid cancer and identified genetic pathways regulating this response. Mammary expression of activated Ras led to the formation of senescent cellular foci in a majority of mice. Deletion of the p19 ARF , p53, or p21 WAF1 tumor suppressors but not p16 INK4a prevented senescence and permitted tumorigenesis. Id1 has been implicated in the control of senescence in vitro, and elevated expression of Id1 is found in a number of solid cancers, so we tested whether overexpression of Id1 regulates senescence in vivo. Although overexpression of Id1 in the mammary epithelium was not sufficient for tumorigenesis, mice with expression of both Id1 and activated Ras developed metastatic cancer. These tumors expressed high levels of p19 Arf , p53, and p21 Waf1 , demonstrating that Id1 acts to make cells refractory to p21 Waf1 -dependent cell cycle arrest. Inactivation of the conditional Id1 allele in established tumors led to widespread senescence within 10 days, tumor growth arrest, and tumor regression in 40% of mice. Mice in which Id1 expression was inactivated also exhibited greatly reduced pulmonary metastatic load. These data demonstrate that established tumors remain sensitive to senescence and that Id1 may be a valuable target for therapy.breast ͉ cancer ͉ metastasis A number of mechanisms act to suppress tumorigenesis, including cell cycle checkpoints, apoptosis, and immune surveillance. Evidence is emerging for a role for cellular senescence as an additional tumor suppressive response to oncogene activation. Oncogene-induced senescence (OIS) was initially described in cultured cells exposed to activated oncogenes and is defined as a proliferative arrest insensitive to mitogenic stimulation. A number of other cellular stresses such as exposure to DNA damaging agents or oxidative stress can also induce a senescence-like state. It is characterized by the expression of markers, including acidic beta-galactosidase (SA-␤Gal) and the CDK inhibitors p21 waf1 and p16 INK4A . Cells undergoing senescence in culture also adopt a distinctive flattened, vacuolar morphology.The molecular sensors of OIS are variously reported to include components of the DNA damage response, the PML protein, and the p16 INK4A or p19 ARF tumor suppressors (reviewed in ref. 1). The retinoblastoma (RB) and p53 tumor suppressor pathways are generally required for the induction of OIS; however, the contribution of either varies between models and appears dependent on the initiating event and the cellular context. In some settings, p16 INK4A is required for OIS, whereas, in others, p19 ARF -p53-p21 waf1 pathway is the essential effector of OIS.Members of the Ras family of small GTPases are frequently involved in cancer, and overexpression or activating mutation of one of the three family members, HRAS, KRAS, and NRAS is found in a wide array of cancers...

NOTCH1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL) and recently have been found in non-small cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated NOTCH1 in the lung by developing a transgenic mouse model in which activated NOTCH1 was overexpressed in the alveolar epithelium. The initial response to activated NOTCH1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas arose in the transgenic mice, but failed to progress to carcinoma. Interestingly, MYC and MYCL1 were expressed in the adenomas, suggesting that selection for enhanced MYC activity may facilitate tumorigenesis. Using mice engineered to co-express activated NOTCH1 and MYC, we found that supplementing MYC expression increased the frequency of N1ICD-induced adenomas and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by MYC and/or activated NOTCH1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated NOTCH1 substitutes for RAS activation in cooperation with MYC in the development of NSCLC. These tumor models should be valuable for exploring the role of activated NOTCH1 in the genesis of NSCLC and for testing therapies targeting either activated NOTCH1 or its downstream effectors.