Fig. 1: Clinically relevant dosing with oxaliplatin drives emergence of drug-resistant, metastatic phenotypes in CRC cell lines.

A Schematic depicting generation of oxaliplatin-resistant models. HCT116 and SW480 CRC cells were treated with 0.5 µM (LD), 5 µM (MD), or 80 µM (HD) of oxaliplatin for 72 h and then left to recover in drug-free medium until confluent. Cells were then replated and treated again with oxaliplatin for 72 h. This dosing regime was repeated for 10 cycles. Oxaliplatin-resistant models were subjected to downstream transcriptomic and phenotypic characterizations. B Representative dose-response curves of oxaliplatin-resistant HCT116 models compared to parental cells (PAR). C Oxaliplatin IC₅₀ fold change in HCT116-LD, MD, and HD relative to PAR. D Transwell invasion assay in HCT116-PAR, LD, MD, and HD. E Transwell migration assay in HCT116-PAR, LD, MD, and HD. F Representative H&E staining for spontaneous metastasis in lung sections from mice harboring xenografts of HCT116-PAR, LD, MD, and HD. F’ Quantification of total tumor nodules area in lung sections of mice harboring xenografts of HCT116 parental and oxaliplatin-resistant models (n = at least 8). G In vivo tumor growth kinetics of HCT116-PAR, LD, MD, and HD xenografts (n = 5). H Corresponding image of HCT116-PAR, LD, MD, and HD xenografts at day 70. I Three representative H&E staining of lung sections in mice harboring HCT116-PAR xenografts treated with either vehicle or oxaliplatin (5 mg/kg). I’ Quantification of tumor nodules area in lung sections from mice harboring HCT116-PAR xenografts treated with vehicle or oxaliplatin (n = 9). Statistical significance was determined using Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test for (C, D, E, F’). Ordinary two-way ANOVA followed by Dunnett’s multiple comparisons test was used for G and two-tailed unpaired t-test for I’. Figure 1A was created with BioRender.com.