A newly developed mouse model may offer a more faithful platform for studying colorectal cancer (CRC), particularly left-sided disease driven by APC mutations. In research published in Cellular and Molecular Gastroenterology and Hepatology, investigators report that colon-specific loss of keratin 8 (K8), combined with monoallelic inactivation of adenomatous polyposis coli (Apc), rapidly induces distal colon adenocarcinomas that mirror key features of human CRC .
CRC models have long relied on carcinogens or germline Apc mutations that predominantly produce tumors in the small intestine rather than the colon. To address this limitation, the researchers used a tamoxifen-inducible, colon epithelium–specific Cre system (CDX2P-CreERT2) to selectively downregulate K8—with or without concurrent Apc inactivation—in adult mice .
K8 is a major intermediate filament protein in simple epithelia and contributes to structural integrity and stress protection. In mice with colon-specific K8 downregulation alone, the authors observed a patchy loss of K8 expression restricted to the colon, sparing the ileum. Within 28 days, K8-negative areas exhibited crypt loss, increased neutrophil infiltration in the proximal colon, and heightened epithelial proliferation, evidenced by elevated Ki67 and phospho-histone H3 staining . These regions also showed reduced IL-22 binding protein and increased STAT3 activation—changes associated with pro-proliferative and pro-tumorigenic signaling .
Notably, the biological consequences differed by colonic region. While the proximal colon demonstrated more inflammation and crypt damage, the distal colon showed features more closely aligned with tumor initiation, including altered beta-catenin localization, expansion of Sox9-positive stem and progenitor cells, and increased asymmetric cell division .
When K8 downregulation was combined with monoallelic Apc inactivation, tumorigenesis was markedly accelerated. By 67 days after induction, all K8flox/flox; CDX2P-CreERT2; Apcflox/+ mice developed multiple tumors in the distal colon, whereas mice with Apc inactivation alone rarely developed tumors . Histologically, the lesions ranged from dysplasia to adenocarcinoma and were largely K8-negative. Tumors demonstrated reduced CDX2 expression and evidence of partial epithelial-to-mesenchymal transition (EMT), including increased vimentin expression and activation of STAT3 and TGF-β–associated pathways .
Importantly, the murine findings were paralleled in human data. Analysis of The Cancer Genome Atlas colon adenocarcinoma cohort via UALCAN revealed significantly reduced K8 transcription in primary tumors compared with normal colon tissue, across stages, nodal status, age groups, and sex . Immunohistochemistry of patient samples confirmed decreased K8 protein expression in adenocarcinoma and adjacent tissue relative to normal epithelium .
Tumors in this model arose predominantly in the distal colon—aligning with the anatomical distribution of many human CRCs—and developed within approximately two months, without carcinogen exposure . The authors conclude that K8 plays a protective, tumor-suppressive role in the colon, with region-specific effects: limiting inflammation proximally and maintaining progenitor cell balance and symmetric division distally.
By recapitulating colon-restricted tumorigenesis driven by Apc alteration and K8 downregulation—both features observed in human disease—this model may serve as a valuable bridge between mechanistic CRC research and preclinical therapeutic testing.