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Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Treatment options for CRC include surgical resection, chemotherapy, targeted therapy and immunotherapy. Unfortunately, even after well-directed curative treatment, some patients experience treatment failure and relapse due to multi-drug resistance, which can be attributed to cancer stem cells (CSCs). With their self-renewal and multi-lineage differentiation capabilities, CSCs play a key role in tumor initiation, therapeutic resistance and metastasis development. However, CSCs represent less than 5% of the tumor mass, which is a challenge for their isolation. The sedimentation field-flow fractionation (SdFFF) technique allows the sorting of homogeneous populations of poorly differentiated or undifferentiated cells according to biophysical characteristics. The objectives of this research project are: (1) to isolate CSCs from cell lines and primary cultures, representative of different stages of CRC using SdFFF, (2) to characterize phenotypically and functionally the sorted fractions (CSC-enriched vs differentiated) in vitro and in vivo, and (3) to analyze the response to chemotherapy of these fractions in 2D and 3D in vitro models. Our phenotypic and functional characterization results confirm the relevance of SdFFF to isolate CSC-enriched fractions. Furthermore, our preliminary results have demonstrated a difference in chemotherapy sensitivity between CSC-enriched and control fractions, as well as between cell lines derived from primary tumors and those derived from CRC metastases, in 2D. Chemosensitivity tests are underway in 3D models and the regulatory pathways that may be associated with chemotherapy resistance will be analyzed. The ultimate goal of this project is to study the therapeutic response of CSC-enriched fractions from CRC patient samples in order to predict treatment efficacy.