作者
Arafath K Najumudeen, Fatih Ceteci, Sigrid K Fey, Gregory Hamm, Rory T Steven, Holly Hall, Chelsea J Nikula, Alex Dexter, Teresa Murta, Alan M Race, David Sumpton, Nikola Vlahov, David M Gay, John RP Knight, Rene Jackstadt, Joshua DG Leach, Rachel A Ridgway, Emma R Johnson, Colin Nixon, Ann Hedley, Kathryn Gilroy, William Clark, Sudhir B Malla, Philip D Dunne, Giovanny Rodriguez-Blanco, Susan E Critchlow, Agata Mrowinska, Gaurav Malviya, Dmitry Solovyev, Gavin Brown, David Y Lewis, Gillian M Mackay, Douglas Strathdee, Saverio Tardito, Eyal Gottlieb, Zoltan Takats, Simon T Barry, Richard JA Goodwin, Josephine Bunch, Martin Bushell, Andrew D Campbell, Owen J Sansom
发表日期
2021/1
期刊
Nature genetics
卷号
53
期号
1
页码范围
16-26
出版商
Nature Publishing Group US
简介
Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of …
学术搜索中的文章
AK Najumudeen, F Ceteci, SK Fey, G Hamm… - Nature genetics, 2021