Cancer cell adaptation to metabolic stress

描述(申请人提供)：在营养充足的条件下，癌细胞可以从胞外葡萄糖和谷氨酰胺合成脂质、核酸和其他大分子。然而，由于侵袭性病变的生长超过了现有肿瘤血管的灌流能力，细胞必须适应氧气和血液中营养物质(即葡萄糖、氨基酸和脂质)的减少才能生存和增殖。总而言之，我们发现了多种癌细胞适应代谢应激的新机制。具体地说，葡萄糖和谷氨酰胺衍生的柠檬酸都不能支持低氧肿瘤微环境中的从头合成脂肪酸，这是因为硬脂酰辅酶A脱饱和酶(SCD1)介导的单不饱和脂肪的产生依赖于O2。相反，低氧癌细胞从外源性来源获得脂质，如血流或细胞外液。虽然长期以来人们一直认识到SCD1催化耗氧酶反应，但观察到生长中的肿瘤显示出O2水平下降到支持SCD1活性的水平以下的区域是新的。这种代谢应激导致内质网内的“不适应”、细胞毒性未折叠蛋白反应(UPR)。在该计划中，三个综合项目将追求以下具体目标：目标1：确定RAS转化的细胞如何获得外源不饱和脂肪酸；“巨噬细胞吞噬”是相关机制吗？此外，还将探讨自噬成分在RAS介导的脂质利用中的作用；目标2：评估低氧条件下不饱和：饱和脂肪酸比例对mTORC1和pVHL调节的细胞存活的影响。不饱和脂肪酸水平的降低会导致UPR介导的细胞死亡，这一机制将在ccRCC细胞和原发患者样本中典型的“造脂”表型中进一步探索；以及目标3：确定PERK激酶抑制是否代表着治疗恶性黑色素瘤的有吸引力的治疗选择。显然，不完全抑制PERK会导致黑色素瘤生长，而抑制50%则会导致黑色素瘤细胞显著死亡。这些发现很重要，因为通过TCGA的努力，现在已经在包括黑色素瘤在内的人类患者样本中发现了PERK功能区的突变。总之，通过这些项目和总体计划，我们将确定癌细胞适应肿瘤微环境压力的重要新机制，并确定这些途径是否可以作为抗癌治疗的靶点。

DESCRIPTION (provided by applicant): In nutrient replete conditions, cancer cells can synthesize lipids, nucleic acids, and other macromolecules from extracellular glucose and glutamine. However, as aggressive lesions overgrow the capacity of existing tumor vasculature to perfuse them, cells must adapt to decreased availability of O2 and blood-born nutrients (i.e. glucose, amino acids, and lipids) to survive and proliferate. Collectively, we have discovered novel mechanisms whereby multiple cancer cell types adapt to metabolic stress. Specifically, neither glucose- nor glutamine-derived citrate can support de novo fatty acid synthesis in hypoxic tumor microenvironments, due to the O2- dependence of stearoyl-CoA desaturase (SCD1)-mediated generation of monounsaturated lipids. Instead, hypoxic cancer cells obtain lipids from exogenous sources, such as the blood stream or extracellular fluid. While it has long been appreciated that SCD1 catalyzes O2-consuming enzymatic reactions, the observation that growing tumors exhibit regions where O2 levels decline below levels supporting SCD1 activity is novel. This metabolic stress results in a "maladaptive", cytotoxic Unfolded Protein Response (UPR) within the ER. In this Program, three integrated Projects will pursue the following specific aims to: Aim 1: Determine how Ras-transformed cells acquire exogenous unsaturated fatty acids; is "macropinocytosis" the relevant mechanism? Moreover, the role of autophagy components in Ras-mediated lipid utilization will be explored; Aim 2: Assess the impact of unsaturated: saturated fatty acid ratios on mTORC1- and pVHL-regulated cell survival under hypoxic conditions. Decreased levels of unsaturated fatty acids result in an UPR-mediated cell death, and this mechanism will be further explored in the "lipogenic" phenotype typical of ccRCC cells and primary patient samples; and Aim 3: Determine if PERK kinase inhibition represents an attractive therapeutic option for treating malignant melanoma. Apparently, incomplete PERK inhibition results in melanoma growth, while e 50% inhibition results in significant melanoma cell death. These findings are important because mutations in PERK functional domains have now been identified in human patient samples through TCGA efforts, including melanoma. Collectively, through these Projects and the Overall Program, we will define important new mechanisms by which cancer cells adapt to tumor microenvironmental stress, and determine whether these pathways can be targeted for anti-cancer treatment.