Metabolic Influences on Complex Tumor Neighborhoods

项目摘要 肾细胞癌是美国十大最常见的恶性肿瘤之一， 自2001年以来，男性和女性的发病率均有所增加。最常见的肾癌亚型是“透明”型， 肾细胞癌（ccRCC）是一种典型的肾细胞癌，约占所有病例的75%。对于早期疾病，外科手术 切除ccRCC可以是治愈性的，尽管对于晚期转移性癌症，存活率显著下降。 ccRCC患者现在可使用多种疗法，包括抗血管生成VEGF/受体酪氨酸 激酶抑制剂、免疫检查点阻断剂、基于mTORC 1的药物和新型HIF-2a抑制剂。 然而，并不是所有的患者都对这些治疗有反应，五年复发率现在接近40%， 这些病例中的大多数发生转移。重要的是，ccRCC缺乏常见的致癌突变 在其他人类癌症中观察到，包括PI 3 K，PTEN，TP 53和KRAS，这阻碍了成功的治疗。 使用相应的靶向治疗。相反，我们产生了拷贝数变异， 转录组学和代谢组学数据，以确定在代谢过程中普遍改变的多种代谢途径。 ccRCC肿瘤。这些包括产酶果糖-1，6-二磷酸1（FBP 1）的损失， 尿素循环酶，包括氨基琥珀酸合成酶1（ASS 1）、氨基琥珀酸裂解酶（ASL）和 核糖核酸酶2（ARG 2）。最后，ccRCC表现出异常高数量的脂滴，脂滴是储存 甘油三酯和胆固醇酯是这种疾病的标志。通过描述分子结果 在这些普遍的代谢变化中，我们已经开发了针对大多数患者的新的治疗策略， 被诊断为肾癌亚型此外，我们的研究结果已经扩展到其他癌症， 作为肝细胞癌（HCC）和软组织肉瘤（STS），这似乎是从事高度相似的， 代谢重编程我们的数据表明，像ABT-263这样的“senolytics”可以部署在 治疗HCC，而ITX-5061，一种HDL胆固醇转运蛋白SCARB 1的抑制剂， 有效治疗ccRCC。结果是范式的转变，因为可以理解的怀疑仍然存在 关于“麻醉”癌症代谢的效用，考虑到代谢的异质性，可塑性， 在各种癌症中观察到的冗余。然而，我们的研究结果使用原位体内肿瘤模型， 为更深入的探索提供了理论基础。正在进行和未来的工作将调查如何一致的代谢 肿瘤实质内的适应影响基质成分，例如成纤维细胞和免疫细胞， 基于一系列互补的体外和体内模型，包括新的原发性HCC， STS小鼠模型和ccRCC和HCC患者来源的异种移植物和类器官。主要概念 我们最近工作的创新之处在于证明了多个代谢网络是一致改变的 （~100%）在遗传多样性癌症（如ccRCC、HCC和STS）中， 可行的治疗策略。

Project Summary Renal cell carcinoma is among the ten most prevalent malignances in the United States, exhibiting an increased incidence in both men and women since 2001. The most common kidney cancer subtype is “clear cell” renal cell carcinoma (ccRCC), which accounts for ~75% of all cases. For early-stage disease, surgical resection of ccRCCs can be curative, although survival drops significantly for advanced, metastatic cancers. Multiple therapies are now available to ccRCC patients, including anti-angiogenic VEGF/receptor tyrosine kinase inhibitors, immune checkpoint blockade, mTORC1-based drugs, and a novel HIF-2a inhibitor. However, not all patients respond to these treatments and five-year relapse rates now approach 40%, and the majority of these cases develop metastases. Importantly, ccRCCs lack common oncogenic mutations observed in other human cancers, including PI3K, PTEN, TP53, and KRAS, which hinders successful treatment using corresponding targeted therapies. Instead, we have generated copy number variation, transcriptomic, and metabolomic data to identify multiple metabolic pathways that are universally altered in ccRCC tumors. These include loss of the gluconeogenic enzyme fructose-1,6-bisphosphate 1 (FBP1) and urea cycle enzymes, including argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL), and arginase 2 (ARG2). Finally, ccRCCs exhibit unusually high numbers of lipid droplets, organelles which store triglycerides and cholesterol esters and a hallmark of this disease. By delineating the molecular consequences of these universal metabolic changes, we have developed new therapeutic strategies to target most patients diagnosed with this kidney cancer subtype. Moreover, our findings have been extended to other cancers such as hepatocellular carcinoma (HCC) and soft tissue sarcoma (STS) which appear to engage in highly similar metabolic reprogramming. Our data demonstrate that “senolytics” like ABT-263 could be deployed for the treatment of HCC, whereas ITX-5061, an inhibitor of the HDL cholesterol transporter SCARB1, may be effective for treating ccRCC. The results are paradigm-shifting in that understandable skepticism remains regarding the utility of “drugging” cancer metabolism, considering the metabolic heterogeneity, plasticity, and redundancy observed in various cancers. However, our results using autochthonous in vivo tumor models provide a rationale for deeper exploration. Ongoing and future work will investigate how consistent metabolic adaptations within the tumor parenchyma impact stromal components, such as fibroblasts and immune cells, based on an arsenal of complementary in vitro and in vivo models, that include novel autochthonous HCC and STS mouse models and ccRCC and HCC patient derived xenografts and organoids. A principal conceptual innovation of our recent work is the demonstration that multiple metabolic networks are consistently altered (~100%) in genetically diverse cancers like ccRCC, HCC, and STS, and the identification of novel, highly feasible therapeutic strategies.