dataset
posted on 2023-03-31, 04:25 authored by Samuel A. Miller, Robert A. Policastro, Shruthi Sriramkumar, Tim Lai, Thomas D. Huntington, Christopher A. Ladaika, Daeho Kim, Chunhai Hao, Gabriel E. Zentner, Heather M. O'Hagan Statistical analysis of TCGA COAD comparing Normal, BRAF mutant, KRAS mutant, and all other tumors.
Funding
Core Pilot Grant
Indiana Clinical and Translational Sciences Institute
NIH
National Center for Advancing Translational Science
Clinical and Translational Sciences Award
National Center for Advancing Translational Sciences
Research Enhancement Grant
Elwert Award
IUSM
IUSCCC P30
Van Andel Institute
Cancer Epigenetics Dream Team
Entertainment Industry Foundation
American Association for Cancer Research
SU2C
History
ARTICLE ABSTRACT
Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer histologic subtypes, their role in colorectal cancer progression has been underexplored. Here, our analysis of The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data demonstrates that EEC progenitor cells are enriched in BRAF-mutant colorectal cancer patient tumors, cell lines, and patient-derived organoids. In BRAF-mutant colorectal cancer, 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. Lysine-specific demethylase 1 (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 colorectal cancer.
This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth.
