Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death worldwide. Somatic mutations promote molecular variation across patients, or inter-tumor heterogeneity, that drives variable patient outcomes. Combinations of mutations can produce novel phenotypes and variability in the efficacy of different therapeutics. However, little is known about how different combinations of mutations affect gene regulatory mechanisms. In this dissertation, I leverage genetically modified organoid models of CRC to investigate how different combinations of CRC driver mutations affect miRNA profiles and transcriptional networks. In Chapter 2, I define mutation-specific patterns of miRNA expression across genetically modified mouse enteroid models. I show that miR-24-3p is aberrantly elevated in mouse enteroid and human colon tumor samples regardless of mutational context. Furthermore, I reveal that genes downregulated in various mutated mouse enteroids, and primary colon tumors are enriched for predicted miR-24-3p target genes. I demonstrate that inhibition of miR-24-3p decreases cell survival in HCT116 and WT mouse enteroids by increasing apoptosis. Predicted targets upregulated in response to miR-24-3p reduction are enriched for regulators of apoptosis. I highlight two post-transcriptionally regulated targets of miR-24-3p (HMOX1, PRSS8), the downregulation of which may contribute to the oncogenic function of miR-24-3p. Chapter 3 expands on my previous work by characterizing genotype-specific miRNA profiles and transcriptional regulatory element (TRE) activity in genetically modified human colonoid models. I highlight a group of miRNAs that are uniquely downregulated in APC/KRAS/TP53 mutant (AKP-mutant) colonoids. MiR-10a-5p and miR-34a-5p are two notable tumor suppressor miRNAs that are affiliated with this group. I demonstrate that most changes in AKP-mutant miRNA expression profiles are concordant with alterations in miRNA transcription. MiR-10a-5p is a notable exception to this trend, suggesting that it is primarily post-transcriptionally regulated in the AKP-mutant context. Additionally, I show that TREs upregulated in AKP-mutant colonoids are enriched for multiple oncogenic transcription factor (TFs) binding sites (HIF-2α, LRF, SP2). Interestingly, these TFs harbor predicted miRNA binding sites for miR-10a-5p and/or miR-34a-5p. Together, my dissertation provides novel insight into how combinations of somatic mutations may promote inter-tumor heterogeneity. Furthermore, I highlight candidate therapeutic targets for the advancement of precision medicine.