Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Molecular Biology and Genetics, Koç University, Istanbul 34450, Turkey.
Dev Cell. 2019 Jan 28;48(2):277-286.e6. doi: 10.1016/j.devcel.2018.12.003. Epub 2019 Jan 10.
Interactions between tumors and host tissues play essential roles in tumor-induced systemic wasting and cancer cachexia, including muscle wasting and lipid loss. However, the pathogenic molecular mechanisms of wasting are still poorly understood. Using a fly model of tumor-induced organ wasting, we observed aberrant MEK activation in both tumors and host tissues of flies bearing gut-yki tumors. We found that host MEK activation results in muscle wasting and lipid loss, while tumor MEK activation is required for tumor growth. Strikingly, host MEK suppression alone is sufficient to abolish the wasting phenotypes without affecting tumor growth. We further uncovered that yki tumors produce the vein (vn) ligand to trigger autonomous Egfr/MEK-induced tumor growth and produce the PDGF- and VEGF-related factor 1 (Pvf1) ligand to non-autonomously activate host Pvr/MEK signaling and wasting. Altogether, our results demonstrate the essential roles and molecular mechanisms of differential MEK activation in tumor-induced host wasting.
肿瘤与宿主组织之间的相互作用在肿瘤诱导的全身消耗和癌症恶病质中起着至关重要的作用，包括肌肉消耗和脂质丢失。然而，消耗的发病分子机制仍知之甚少。使用诱导器官消耗的果蝇模型，我们观察到携带肠道-yki 肿瘤的果蝇的肿瘤和宿主组织中存在异常的 MEK 激活。我们发现宿主 MEK 激活导致肌肉消耗和脂质丢失，而肿瘤 MEK 激活是肿瘤生长所必需的。引人注目的是，单独抑制宿主 MEK 就足以消除消耗表型，而不影响肿瘤生长。我们进一步发现，yki 肿瘤产生了血管（vn）配体，以触发自主 Egfr/MEK 诱导的肿瘤生长，并产生 PDGF 和 VEGF 相关因子 1（Pvf1）配体，以非自主方式激活宿主 Pvr/MEK 信号和消耗。总之，我们的结果表明，在肿瘤诱导的宿主消耗中，差异 MEK 激活的重要作用和分子机制。
