In a groundbreaking study set to reshape our understanding of colorectal cancer (CRC) progression, researchers have uncovered how the loss of colonic cellular identity fuels tumor plasticity and metastasis. This research highlights the critical role of the chromatin remodeller ATRX and lineage-specifying transcription factors in maintaining the colonic epithelial phenotype and suppressing squamous-like transitions that drive aggressive cancer behaviors. The findings present a compelling narrative of how disruption in cellular fidelity in CRC underlies the emergence of distinct tumor subtypes associated with poor patient prognosis.
The investigation began by examining the expression patterns of ATRX alongside key colonic lineage regulators HNF4A and CDX2 in human CRC tissue samples. Utilizing a tissue microarray (TMA) spanning stages I to III of primary tumors, the team demonstrated a significant correlation in the expression of these proteins, mirroring observations from parallel mouse models. Importantly, tumors exhibiting higher levels of LY6D, a marker of squamous-like cells, showed diminished expression of ATRX, HNF4A, and CDX2. This inverse relationship suggests that ATRX and related factors enforce lineage fidelity, whose loss is permissive for squamous-like plasticity within the tumor microenvironment.
Pushing the envelope further, researchers analyzed matched patient samples from primary tumors and liver metastases to chart the progression of these lineage changes during advanced disease stages. The prevalence of squamous-like cells, demarcated by LY6D and KRT5 staining, rose significantly in stage IV tumors relative to earlier stages. Strikingly, the abundance of these cells in metastatic liver lesions closely mirrored their matched primary tumors, indicating that squamous-like phenotypes are not a consequence of metastatic colonization but rather are pre-established in the primary tumor mass. Accompanying this phenotypic shift, a modest but significant decline in HNF4A and ATRX expression in liver metastases underscores a progressive erosion of colonic identity concurrent with disease advancement.
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To provide mechanistic validation, the team utilized cutting-edge patient-derived CRC organoids to model the impact of ATRX loss in vitro. Genetic ablation of ATRX in these organoids resulted in a conspicuous downregulation of colonic epithelial markers such as HNF4A and CDX1, alongside an upregulation of squamous-like markers including KRT5. Further, ATRX knockout organoids displayed heightened sensitivity to TGFβ-induced epithelial-to-mesenchymal transition (EMT), reinforcing ATRX’s crucial role in maintaining epithelial lineage constraints and suppressing phenotypic plasticity crucial for metastasis.
Linking these molecular insights to clinical phenotypes, the research team leveraged large-scale transcriptomic datasets to interrogate the intrinsic consensus molecular subtypes (iCMS) of CRC. Distinct molecular clusters emerged when stratifying tumors using ATRX-associated squamous-like and colonic epithelial expression signatures derived from their murine CRC model. Tumors with elevated squamous-like gene expression (HiSquam cluster) were enriched for right-sided tumor location, mismatch repair deficiency, and oncogenic BRAF mutations—all features indicative of a more aggressive clinical course. Notably, HiSquam cluster expression portended significantly worse overall survival, underscoring the prognostic potential of ATRX-controlled transcriptional states.
Moreover, epigenomic analysis provided a chromatin-based dimension to these transcriptional changes. By integrating ATAC-seq data from human CRC samples, researchers identified a conspicuous loss of chromatin accessibility at regulatory regions harboring motifs for epithelial lineage transcription factors including HNF4A and CDX2 in tumors with high squamous-like expression. This chromatin remodeling aligns with the transcriptional shift away from colonic identity and highlights the role of chromatin architecture in dictating lineage plasticity and tumor progression.
The implications of these findings extend beyond molecular characterization, offering a fresh understanding of how colorectal tumors exploit lineage infidelity to broaden phenotypic diversity and metastatic potential. By identifying ATRX as a linchpin maintaining colonic epithelial integrity, the study opens avenues for therapeutic interventions designed to restore lineage fidelity or target squamous-like plasticity. The link between ATRX mutations—more prevalent in aggressive CRC subtypes—and poor clinical outcomes positions ATRX-associated profiles as candidate biomarkers for risk stratification and treatment personalization.
Adding a layer of complexity, the detection of hybrid squamous-like tumor cells expressing both LY6D and EPCAM in primary human CRC specimens validates the existence of intermediary cellular states that may facilitate phenotypic plasticity and tumor heterogeneity. This hybrid population could represent a reservoir for therapeutic resistance and metastatic dissemination, warranting further exploration into their biological properties and vulnerabilities.
Notably, the study underscores that squamous-like plasticity is not a mere artifact of metastatic spread but is a characteristic ingrained early in the tumor hierarchy. This challenges existing paradigms about the temporal emergence of aggressive phenotypes in CRC, shifting focus to interventions at earlier disease stages aimed at preserving lineage fidelity and constraining plasticity-driven progression.
In conclusion, this comprehensive investigation delineates a mechanistic cascade whereby loss of ATRX function dismantles a transcriptional and epigenomic network responsible for sustaining colonic epithelial identity. This breakdown unleashes squamous-like multilineage plasticity, fostering aggressive tumor phenotypes and metastasis. By linking molecular alterations to clinical staging, subtype classification, and survival outcomes, the research offers a new conceptual framework for understanding and potentially disrupting colorectal cancer evolution. As such, ATRX and its downstream transcriptional programs emerge as critical targets for future diagnostic and therapeutic strategies aimed at halting the progression of this common and often fatal malignancy.
Subject of Research: Loss of colonic epithelial lineage fidelity in colorectal cancer and its role in tumor plasticity and metastasis.
Article Title: Loss of colonic fidelity enables multilineage plasticity and metastasis.
Article References:
Cammareri, P., Raponi, M., Hong, Y. et al. Loss of colonic fidelity enables multilineage plasticity and metastasis. Nature (2025). https://doi.org/10.1038/s41586-025-09125-5
Image Credits: AI Generated
Tags: chromatin remodelling and cancercolonic epithelial phenotype maintenancecolorectal cancer progressionexpression patterns in CRC tissuelineage-specifying transcription factors in cancermetastasis in colorectal cancermicroarray analysis in colorectal studiespatient sample analysis in cancer researchpoor prognosis tumor subtypesrole of ATRX in cancersquamous-like transitions in tumorstumor plasticity in CRC
