Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain.
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Cancer Res. 2021 Jan 15;81(2):438-451. doi: 10.1158/0008-5472.CAN-20-0622. Epub 2020 Nov 23.
Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFβ/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis. SIGNIFICANCE: Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/438/F1.large.jpg.
肿瘤是由转化的上皮细胞以及促进上皮肿瘤细胞侵袭的肿瘤激活成纤维细胞（CAF）组成的复杂组织。我们在这里表明，CAF 和其他间质细胞比上皮肿瘤细胞更依赖于谷氨酰胺；因此，它们对谷氨酰胺酶的抑制更为敏感。当在低谷氨酰胺条件下培养时，谷氨酰胺依赖性会驱使 CAF 向这种氨基酸迁移。CAF 还可以沿着谷氨酰胺浓度梯度穿过 Matrigel 基质，并在两种细胞共培养时增强肿瘤细胞的侵袭。因此，谷氨酰胺可以指导免疫缺陷小鼠异种移植肿瘤的侵袭。成纤维细胞刺激谷氨酰胺驱动的上皮肿瘤侵袭需要先前的 CAF 激活，这涉及 TGFβ/Snail1 信号轴。CAF 向 Gln 移动时呈现出极化的 Akt2 分布，该分布受迁移前沿中 Gln 依赖性 TRAF6 和 p62 的活性调节，并且这些蛋白质的耗竭会阻止 Akt2 极化和 Gln 驱动的 CAF 侵袭。我们的结果表明，谷氨酰胺剥夺促进 CAF 迁移和侵袭，这反过来又促进肿瘤上皮细胞向富含营养的区域移动。这些结果提供了一种新的分子机制，说明了代谢应激如何增强侵袭和转移。意义：肿瘤相关成纤维细胞向游离谷氨酰胺迁移和侵袭，并促进肿瘤上皮细胞的侵袭，解释了它们从肿瘤恶劣环境向富含营养的相邻组织的运动。
