Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

Metastasis is the leading cause of cancer-related mortality. Cancer stem cells contribute to metastasis in the murine colon cancer models, but the underlying mechanisms are unclear. Here we report a Wnt ligand, Dickkopf2 (DKK2) is essential for colorectal cancer stemness. Genetic depletion of Dkk2 in intestinal epithelial or stem cells reduced tumorigenesis as well as expression of the stem cell marker gene Lgr5 in a model of colitis-associated cancer. Mechanistically, DKK2 activates c-Src followed by increased LGR5 expressing stem cells in colorectal cancer through degradation of HNF4α1. Splenic injection of DKK2-deficient cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases compared to the control cancer organoids in spite of the presence of oncogenic mutations in Apc, Kras and Tp53 genes. These findings suggest that DKK2 is required for stemness of colorectal cancer cells, which in turn contributes to metastasis. Two replicates from normal C57BL/6 murine colonic organoids, colon cancer organoids carrying mutations in Apc, Kras and Tp53 genes and Dkk2 knockout colon cancer organoids with identical oncogenic mutations, respectively.

肿瘤转移是癌症相关死亡的首要诱因。在小鼠结肠癌模型中，癌症干细胞（cancer stem cells）可促进肿瘤转移，但具体潜在机制尚未明确。本研究证实，Wnt配体Dickkopf2（DKK2）对结直肠癌干细胞干性至关重要。在结肠炎相关癌症模型中，肠上皮细胞或干细胞内的Dkk2基因敲除可降低肿瘤发生风险，并下调干细胞标志物基因Lgr5的表达水平。机制层面，DKK2可通过降解HNF4α1激活c-Src通路，进而增加结直肠癌中表达LGR5的干细胞群体。向C57BL/6小鼠脾脏注射DKK2缺陷型癌症类器官（organoids），相较于对照组类器官，即便对照组携带Apc、Kras及Tp53致癌突变，其肝脏转移负荷仍显著降低。上述研究结果表明，DKK2是结直肠癌细胞维持干性的必需因子，而这一过程反过来会促进肿瘤转移。本数据集分别包含取自正常C57BL/6小鼠结肠类器官、携带Apc、Kras和Tp53基因突变的结直肠癌类器官，以及携带相同致癌突变的Dkk2敲除结直肠癌类器官的两份生物学重复样本。