Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.
结直肠癌是全球癌症相关死亡的主要原因之一。根据癌症干细胞模型，高死亡率与转移性疾病直接相关，而转移被认为是由结肠癌干细胞启动的。因此，早期识别具有高转移风险的患者对于改善治疗和患者预后至关重要。转移相关结肠癌基因1是一种独立于肿瘤分期的新型预后生物标志物，可预测肿瘤进展和转移形成。我们先前在MACC1转基因小鼠模型中发现MACC1参与小鼠肠道癌症干性。然而，MACC1在人类癌症干细胞中的表达及其潜在影响尚不明确。本研究基于患者来源肿瘤类器官、患者来源异种移植模型及人类结直肠癌细胞系，探讨了MACC1调控干性和癌症干细胞相关侵袭表型的分子机制。研究发现，来自PDO模型的CD44富集癌症干细胞表达显著更高水平的MACC1和LGR5，并在免疫缺陷小鼠中表现出更强的致瘤性。同样，对PDO和PDX模型进行的RNA测序显示ALDH1(+)癌症干细胞中MACC1表达显著增加，突显其在癌症干性中的作用。我们进一步证实了PDO模型及已建立细胞系中MACC1与癌症干细胞标志物CD44、NANOG和LGR5的相关性。此外，MACC1能增强干细胞基因表达、克隆形成能力和球体形成能力。值得注意的是，我们发现MACC1作为转录因子与LGR5基因启动子结合，揭示了长期公认的癌症干细胞标志物LGR5是MACC1诱导人类结直肠癌患者癌症干细胞样特性的新型关键信号介质。结直肠癌细胞系及患者肿瘤组织中MACC1与LGR5的显著正相关性进一步证实了我们的体外研究结果。综上所述，本研究表明转移诱导因子MACC1可作为癌症干细胞相关标志物。靶向MACC1的干预策略有望改善结直肠癌患者的靶向治疗，从而根除癌症干细胞并预防癌症复发和远处转移形成。
MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer
肿瘤(癌症)患者之家