Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, 4362, Esch-sur-Alzette, Luxembourg.
Biochem Soc Trans. 2021 Feb 26;49(1):467-476. doi: 10.1042/BST20200964.
Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.
癌症干细胞（CSC）可能是最相关和难以捉摸的癌细胞群体，因为它们具有产生新肿瘤的精湛能力。可以合理地假设，高度突变的癌症基因，如 KRAS，在功能上与有助于出现干细胞特征的过程相关。在这篇综述中，我们将总结致癌 Ras 具有干细胞驱动活性的证据。这种活性似乎因 Ras 同工型而异，高度突变的 KRAS 具有特别深远的影响。除了 Wnt 和 Hedgehog (Hh) 等已确立的干细胞途径外，MAPK 途径的精确、细胞周期依赖性协调似乎在这种情况下传递 Ras 激活。我们将研究 K-Ras4B（以下简称 K-Ras）的非典型活性如何通过其贩运伴侣钙调蛋白和 PDE6D/PDEδ 来实现。两者都动态定位于与细胞命运决定密切相关的细胞机制，例如初级纤毛和中心体。因此，可以推测致癌 K-Ras 破坏了在细胞分化过程中必需的基本极化信号和不对称分配过程。
