Simple Summary: Colorectal cancer is one of the most frequent types of cancer world-wide, leading to over 500,000 cancer-related deaths each year. Although many primary colorectal cancer patients can be cured by surgery, up to 60% will develop metastases. Chemotherapeutic strategies are well-established, but finally often lead to chemo-resistance and tumor relapse. A specific chemotherapeutic approach is low dose metronomic (LDM) therapy, which is based on a constant administration of low doses of a chemotherapeutic compound instead of high-dose pulses, which are often a huge burden for patients and also may induce rapid resistance. However, the molecular mechanism of LDM chemotherapy is not fully understood. Our study therefore aims at identifying gene signatures of colorectal cancer progression under LDM chemotherapy which eventually provides new potential biomarkers for therapeutic interventions. Understanding the molecular signatures of colorectal cancer progression under chemotherapeutic treatment will be crucial for the success of future therapy improvements. Here, we used a xenograft-based mouse model to investigate, how whole transcriptome signatures change during metastatic colorectal cancer progression and how such signatures are affected by LDM chemotherapy using RNA sequencing. We characterized mRNAs as well as non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs in colorectal-cancer bearing mice with or without LDM chemotherapy. Furthermore, we found that circZNF609 functions as oncogene, since over-expression studies lead to an increased tumor growth while specific knock down results in smaller tumors. Our data represent novel insights into the relevance of non-coding and circRNAs in colorectal cancer and provide a comprehensive resource of gene expression changes in primary tumors and metastases. In addition, we present candidate genes that could be important modulators for successful LDM chemotherapy.