An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer
- 1Botnar Institute of Immune Engineering
Abstract
Genomic stratification leaves most patients with colorectal cancer (CRC) without opportunities for targeted therapy. Seeking tumour state-linked drug sensitivities, we combined image-based ex vivo drug profiling with matched transcriptomics in 127 prospectively collected patient biopsies across CRC stages and molecular subtypes. Network-level integration identified a ciliogenic cell state defined by upregulation of cilia related genes with selective sensitivity to the FGFR inhibitor erdafitinib. This ciliogenic signature was associated with poor progression-free survival (hazard ratio 2.28; adjusted p=0.0098), even in early-stage colorectal cancer. Furthermore, knockdown of the transcriptional regulators RFX2 and RFX3, upstream of the ciliogenic cell state, attenuated erdafitinib sensitivity. Orthogonal bulk and single-cell analyses across normal, primary and metastatic tissues contextualised the ciliogenic programme along a transition from canonical epithelial states towards fetal and non-canonical tumour states, concomitant with Wnt-related remodelling, FGFR1/FGFR2 upregulation, and loss of intestinal epithelial identity. Together, these findings define a tumour-intrinsic ciliogenic cell state as a feature of CRC progression, revealing a patient-stratified repurposing opportunity for targeted therapy beyond the current CRC treatment paradigms.
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BibTeX
@misc{kralickova2026rfxdriven,
title = {{An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer}},
author = {L. Kralickova and N. Miglino and C. Esposito and R. Pfaendler and R. Wegmann and P. Ballesteros Cuartero and J. Mena and F. Panebianco and L. A. Boos and U. Richter and P. Rahimzadeh and T. Mehra and V. H. Koelzer and S. Piscuoglio and A. Wicki and B. Snijder},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.756637},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.756637v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer
AU - L. Kralickova
AU - N. Miglino
AU - C. Esposito
AU - R. Pfaendler
AU - R. Wegmann
AU - P. Ballesteros Cuartero
AU - J. Mena
AU - F. Panebianco
AU - L. A. Boos
AU - U. Richter
AU - P. Rahimzadeh
AU - T. Mehra
AU - V. H. Koelzer
AU - S. Piscuoglio
AU - A. Wicki
AU - B. Snijder
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.756637
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.756637v1
AB - Genomic stratification leaves most patients with colorectal cancer (CRC) without opportunities for targeted therapy. Seeking tumour state-linked drug sensitivities, we combined image-based ex vivo drug profiling with matched transcriptomics in 127 prospectively collected patient biopsies across CRC stages and molecular subtypes. Network-level integration identified a ciliogenic cell state defined by upregulation of cilia related genes with selective sensitivity to the FGFR inhibitor erdafitinib. This ciliogenic signature was associated with poor progression-free survival (hazard ratio 2.28; adjusted p=0.0098), even in early-stage colorectal cancer. Furthermore, knockdown of the transcriptional regulators RFX2 and RFX3, upstream of the ciliogenic cell state, attenuated erdafitinib sensitivity. Orthogonal bulk and single-cell analyses across normal, primary and metastatic tissues contextualised the ciliogenic programme along a transition from canonical epithelial states towards fetal and non-canonical tumour states, concomitant with Wnt-related remodelling, FGFR1/FGFR2 upregulation, and loss of intestinal epithelial identity. Together, these findings define a tumour-intrinsic ciliogenic cell state as a feature of CRC progression, revealing a patient-stratified repurposing opportunity for targeted therapy beyond the current CRC treatment paradigms.
ER -