An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer
Year: 2026
Type: preprint
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 Wntrelated 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.
Institutions: ETH Zurich, Institute for Molecular Systems Biology, University of Zurich, University Hospital Zurich, University of Basel, Thermo Fisher Scientific (United States), University Hospital of Basel, Humanitas University, IRCCS Humanitas Research Hospital, SIB Swiss Institute of Bioinformatics
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221646633