Identifying targetable metabolic dependencies across colorectal cancer progression-猫眼课题宝

DOI：

10.1101/2022.03.23.485483

发表时间：

2023-10

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

D. Legge;Ewelina Stanko;Amy K. Holt;C. Bull;T. Collard;Madhu Kollareddy;Jacob Bellamy;Sarah Groves;Eric H. Ma;E. Hazelwood;D. Qualtrough;B. Amulic;K. Malik;Ann C. Williams;Nicholas Jones;E. Vincent

结直肠癌(CRC)是一个多阶段的过程，从良性腺瘤形成，发展到浸润性癌，最后转移。肿瘤细胞必须调整它们的新陈代谢，以支持与疾病进展相关的能量和生物合成需求。因此，靶向癌细胞代谢是治疗结直肠癌的一条很有前途的途径。然而，为了识别特定于结直肠癌阶段的易受处理的代谢易损性结节，我们必须了解结直肠癌发生过程中代谢的变化。在这里，我们使用了一个独特的模型系统--从人类早期腺瘤到晚期腺癌。我们发现，腺瘤细胞在肿瘤进展的早期阶段转变为糖酵解升高，但维持氧化代谢。进展期的腺癌细胞更多地依赖谷氨酰胺衍生的碳来支持TCA循环，而在早期的腺瘤细胞中，糖酵解和TCA循环活性仍然紧密相连。腺癌细胞在燃料来源方面更加灵活，使它们能够在营养不良的环境中增殖。尽管有这种可塑性，我们发现天冬酰胺(ASN)合成是晚期腺癌细胞代谢易损性的一个节点。我们发现，天冬酰胺合成酶(ASNS)的缺失阻止了它们的增殖，而早期的腺瘤细胞在很大程度上对ASN的剥夺具有抵抗力。从机制上讲，我们表明晚期腺癌细胞依赖ASNS来支持mTORC1信号转导以及最大的糖酵解和氧化能力。早期腺瘤细胞对ASN丢失的抵抗力可能是由于在晚期细胞中没有反馈环，使它们能够感知和调节ASN水平，并通过自噬补充ASN。总而言之，我们的研究定义了结直肠癌发展过程中的代谢变化，并强调ASN合成是晚期疾病的靶向代谢易损性。

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Identifying targetable metabolic dependencies across colorectal cancer progression

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