Inflammation is an essential trigger for POLE-driven ultramutated colorectal cancer
- 1UT Southwestern Medical Center
Abstract
Pathogenic variants in the exonuclease (proofreading) domain of DNA polymerase {varepsilon} (POLE) are frequently detected in colorectal cancers (CRC) with high tumor mutational burden (TMB), yet their functional role in intestinal tumorigenesis remains unknown. Here, we investigated the impact of mutation in POLE on intestinal homeostasis using a conditional mouse model expressing the PoleP286R pathogenic driver in intestinal epithelial cells. PoleP286R mutant mice developed invasive adenocarcinomas in the small intestine with incomplete penetrance and extremely long latency but did not spontaneously develop colorectal tumors. However, induction of colitis with dextran sodium sulfate (DSS) resulted in a striking phenotypic shift to colorectal adenocarcinomas at high frequency. Molecular and histological analyses revealed hyperactivation of Wnt/{beta}-catenin, NF-{kappa}B, ERK and STAT3 pathways, accompanied by markedly higher proliferation of intestinal epithelial cells, in DSS-treated PoleP286R mutant mouse colons. Whole genome sequencing of the tumor demonstrated exceptionally high TMB (>100 mutations/megabase) and characteristic trinucleotide signatures, consistent with human POLE tumors. Recurrent mutations in Apc and Ctnnb1 underscored the central role of Wnt signaling in POLE-driven hypermutated CRC. In addition, intestinal organoids derived from PoleP286R mutant mice exhibited accelerated growth and increased expression of pro-proliferative genes. Together, these findings highlight POLE as a gatekeeper of intestinal genomic integrity and identify inflammation as the key driver that unleashes POLE-mutant CRC. Furthermore, this work establishes a mechanistically faithful preclinical platform for studying the molecular pathogenesis of CRC and advancing therapeutic drug discovery.
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BibTeX
@misc{mustofa2026inflammation,
title = {{Inflammation is an essential trigger for POLE-driven ultramutated colorectal cancer}},
author = {M. K. Mustofa and M. Aguilar and H. Zhang and D. Sarkar and S. Roy and M. Alam and M. Basher and S. Sahoo and E. A. Akbay and D. H. Castrillon and H. Zaki},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760274},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760274v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Inflammation is an essential trigger for POLE-driven ultramutated colorectal cancer
AU - M. K. Mustofa
AU - M. Aguilar
AU - H. Zhang
AU - D. Sarkar
AU - S. Roy
AU - M. Alam
AU - M. Basher
AU - S. Sahoo
AU - E. A. Akbay
AU - D. H. Castrillon
AU - H. Zaki
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760274
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760274v1
AB - Pathogenic variants in the exonuclease (proofreading) domain of DNA polymerase {varepsilon} (POLE) are frequently detected in colorectal cancers (CRC) with high tumor mutational burden (TMB), yet their functional role in intestinal tumorigenesis remains unknown. Here, we investigated the impact of mutation in POLE on intestinal homeostasis using a conditional mouse model expressing the PoleP286R pathogenic driver in intestinal epithelial cells. PoleP286R mutant mice developed invasive adenocarcinomas in the small intestine with incomplete penetrance and extremely long latency but did not spontaneously develop colorectal tumors. However, induction of colitis with dextran sodium sulfate (DSS) resulted in a striking phenotypic shift to colorectal adenocarcinomas at high frequency. Molecular and histological analyses revealed hyperactivation of Wnt/{beta}-catenin, NF-{kappa}B, ERK and STAT3 pathways, accompanied by markedly higher proliferation of intestinal epithelial cells, in DSS-treated PoleP286R mutant mouse colons. Whole genome sequencing of the tumor demonstrated exceptionally high TMB (>100 mutations/megabase) and characteristic trinucleotide signatures, consistent with human POLE tumors. Recurrent mutations in Apc and Ctnnb1 underscored the central role of Wnt signaling in POLE-driven hypermutated CRC. In addition, intestinal organoids derived from PoleP286R mutant mice exhibited accelerated growth and increased expression of pro-proliferative genes. Together, these findings highlight POLE as a gatekeeper of intestinal genomic integrity and identify inflammation as the key driver that unleashes POLE-mutant CRC. Furthermore, this work establishes a mechanistically faithful preclinical platform for studying the molecular pathogenesis of CRC and advancing therapeutic drug discovery.
ER -