Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer (CRC) histological subtypes, their role in CRC progression has been underexplored. Here, our analysis of TCGA and single-cell RNA-seq data demonstrates that EEC progenitor cells are enriched in BRAF mutant CRC patient tumors, cell lines, and patient-derived organoids. In BRAF mutant CRC, EEC progenitors were blocked from differentiating further by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of intermediate EECs. Mechanistically, secretory cells and the factors they secrete, such as Trefoil factor 3, promoted colony formation and activation of cell survival pathways in the entire cell population. LSD1 was identified as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss blocks formation of EEC progenitors and reduces tumor growth and metastasis. These findings reveal an important role for EEC progenitors in supporting CRC.