Abstract 2856: Pks+ E. coli trigger intestinal stem cell plasticity and early onset colorectal cancer
Bibliographic record
Abstract
Escherichia coli (E.coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin associated with pathogenesis of colorectal cancer (CRC). The colibactin polyketide induces DNA damage through direct alkylation of DNA, which leads to characteristic mutational A-T rich signatures in the genome (SBS28 and SBS88) that can be identified by whole genome sequencing (WGS). Since WGS is not routinely used clinically, we developed an approach to specifically identify SBS-pks using a clinical targeted exon capture assay, MSK-IMPACT. In an institutional pan-cancer clinical cohort of 78,905 tumors we identified 15,967 samples with >20 mutations detected by MSK-IMPACT. We identified 149/1845 samples with microsatellite stable CRC with >10% mutations attributable to SBS-pks. Examining clinicopathologic and genomic features of SBS-pks+ compared to SBS-pks- CRC tumors, we find that SBS-pks+ signatures are significantly enriched in younger age of onset compared to SBS-pks- CRC patients (median age 52 vs 57, p=0.00059). While global genomic features and oncogenic pathways are similar, we find that the APC:c835-8A>G splice site mutation is overrepresented in SBS-pks+ tumors with 21.7% enrichment compared to 4.99% in SBS-pks- tumors, even further enriched in young onset SBS-pks+ CRC (27% <50 y, 31% <45 y, p<0.0001). To mechanistically investigate colibactin-associated damage we developed a novel long-term human colon organoid-microbe co-culture model system that takes advantage of reversal of polarity in suspension culture. WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E.coli NC101 confirmed induction of SBS-pks signatures, validating the model. 48h acute exposure to pks+ E.coli upregulates DNA replication and DNA damage repair (DDR) pathways coupled with cell cycle stalling in S phase with activation of ATM/ATR, indicative of replication stress. Strikingly, pks+ E.coli exposure drives a phenotypic shift of tumor and normal epithelial cells into an intestinal stem cell (ISC) state, with pks+ exposed cells demonstrating increased regeneration and proliferation, while thermal proximity coaggregation-MS analysis of protein complexes reveals global chromatin remodeling changes. Thus, our findings suggest that colibactin SBS signature is associated with young onset CRC and that the colibactin genotoxin phenotypically promotes cells to enter a proliferative intestinal stem cell states as precursors to CRC carcinogenesis. Correlating our clinicogenomic findings of an increased pks+ signature presence in young onset patients, we propose a model of colibactin injury in which younger, DNA replication and repair proficient cells are able to overcome colibactin-associated DDR stress, while aged colonic cells exit DDR stress through cell cycle arrest and apoptosis, resulting in the overall observed enriched genomic colibactin signature in young onset CRC. Citation Format: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Krystal Lum, Christopher Cowley, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Asha Saxena, Tavis J. Reed, Andrea Cercek, Rona Yaeger, Ileana Cristea, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh. Pks+ E. coli trigger intestinal stem cell plasticity and early onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2856.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".