Research Career Scientist Award

癌细胞对其新陈代谢进行重新编程，以满足其增殖和生存所需的合成代谢过程。 癌细胞重新编程新陈代谢的一种方式是劫持进化保守的新陈代谢 PI3K/Akt/mTORC1信号通路的功能。另一种方法是显著提高基因的表达 己糖激酶亚型，HK2，催化葡萄糖代谢的第一步。的长期目标是 这项拨款申请是为了克服针对癌症新陈代谢和Akt用于癌症治疗的挑战。 虽然癌细胞由于其高葡萄糖代谢(FDG-PET扫描)而可以被选择性地检测到， 利用这一特性进行选择性靶向是具有挑战性的，因为干扰葡萄糖代谢可能 会产生不利的后果。我们克服了这一障碍，证明了己糖激酶2，它催化 糖酵解的第一步，在肿瘤细胞中选择性表达，在小鼠身上可以系统地删除 没有任何不良后果。这项建议是基于我在蜂窝和 生物体水平，并解决以下范式转变：(I)己糖激酶2的胚系缺失，这是 在癌细胞中显著升高，对胚胎是致命的。然而，我们发现在成年小鼠中它的系统性缺失 耐受性良好，在几种癌症小鼠模型中具有治疗作用。这项赠款申请将具体地 阐述己糖激酶2在肿瘤转移中的作用。我们将研究己糖激酶2在EMT和ECT中的作用 通过一种新的机制转移。(Ii)Akt可能是人类最常被激活的癌蛋白 癌症。然而，我们发现，矛盾的是，小鼠肝脏Akt1和Akt2基因的缺失会导致肝脏损伤， 炎症和肝细胞癌的早期发病。我们将确定肝癌细胞如何存活和 在没有Akt的情况下增殖。(Iii)我们发现成年小鼠体内Akt1和Akt2基因的系统性缺失 小鼠的Akt2缺乏可能促进肿瘤的发生和增加化学物质的转移。 诱发肝细胞癌，可能是因为高胰岛素血症。因此，我们启动了一项全面的方法，其中 AKT1或Akt2或两者都可以在肿瘤后以细胞自主方式或系统方式有条件地删除 发病时，跟踪肿瘤的生长和转移。我们的发现显示出显著的和意想不到的差异 与肿瘤发生和发展相关的Akt亚型的细胞自主性与系统性缺失。(四) AMPK的抑制被认为是促肿瘤的。矛盾的是，我们发现AMPK的激活是必需的 用于实体瘤形成和可能转移过程中的细胞存活。我们将勾勒出AMPK在 乳腺癌和前列腺癌在人类细胞和小鼠模型中的转移。我们预计，拟议的 研究将揭示与癌症新陈代谢相关的肿瘤发生的新机制，产生 利用癌症代谢进行癌症治疗，发现癌症表现为过度激活的弱点 PI3K/Akt信号通路。

Cancer cells reprogram their metabolism to fuel anabolic processes required for their proliferation and survival. One way by which cancer cells reprogram metabolism is by hijacking the evolutionarily conserved metabolic function of the PI3K/Akt/mTORC1 signaling pathway. Another way is by markedly elevating the expression of the hexokinase isoform, HK2, which catalyzes the first committed step in glucose metabolism. The long-term goal of this grant application is to overcome challenges in targeting cancer metabolism and Akt for cancer therapy. Although cancer cells can be selectively detected because of their high glucose metabolism (FDG-PET scan), exploiting this property for selective targeting is challenging because interference with glucose metabolism could have adverse consequences. We overcame this roadblock by showing that hexokinase 2, which catalyzes the first committed step in glycolysis, and is selectively expressed in cancer cells, can be systemically deleted in mice without any adverse consequences. The proposal is based on findings made in my laboratory at the cellular and organismal levels, and address the following paradigm shifts: (i) Germ-line deletion of hexokinase 2, which is markedly elevated in cancer cells, is embryonic lethal. However, we found that its systemic deletion in adult mice is well tolerated, and therapeutic in several mouse models of cancer. This grant application will specifically address the role of hexokinase 2 in metastasis. We will investigate the role of hexokinase 2 in EMT and metastasis through a novel mechanism. (ii) Akt is perhaps the most frequently activated oncoprotein in human cancer. However, we found that, paradoxically, hepatic deletion of Akt1 and Akt2 in mice induces liver injury, inflammation, and early onset of hepatocellular carcinoma. We will determine how the HCC cells survive and proliferate in the absence of Akt. (iii) We found that systemic deletion of Akt1 and Akt2 in adult mice elicits rapid mortality, and that Akt2 deficiency in mice could be pro-tumorigenic and increased metastasis of chemically- induced HCC, possibly because of hyperinsulinemia. Therefore, we launched a comprehensive approach in which Akt1 or Akt2 or both can be conditionally deleted either in a cell autonomous manner or systemically, after tumor onset, to follow tumor growth and metastasis. Our findings showed marked and unexpected differences between cell autonomous versus systemic deletions of Akt isoforms with respect to tumor initiation and progression. (iv) The inhibition of AMPK is considered pro-tumorigenic. Paradoxically, we found that AMPK activation is required for cell survival during solid tumor formation and possibly metastasis. We will delineate the role of AMPK during metastasis in human cells and mouse models of breast and prostate cancer. We anticipate that the proposed studies will uncover new mechanisms of tumorigenesis associated with cancer metabolism, yield strategies that exploit cancer metabolism for cancer therapy, and uncover vulnerabilities of cancers displaying hyperactivation of PI3K/Akt signaling.