Targeting IGF2BP1 Creates a Mitotic Vulnerability in Colorectal Carcinoma
- 1Martin-Luther-University Halle-Wittenberg
Abstract
Background Mitotic dysregulation is a common feature of colorectal cancer (CRC), yet the contribution of post-transcriptional mechanisms remain incompletely understood. We investigated how the oncofetal RNA-binding protein IGF2BP1 supports mitotic integrity and exposes therapeutic vulnerabilities in CRC. Methods We integrated patient cohort analyses with genetic and pharmacological perturbation of IGF2BP1, transcriptomics, proteomics, RNA-binding assays and functional studies. Xenografts assessed tumor formation, while BTYNB-paclitaxel responses were examined in CRC cell lines and patient-derived organoids. Results IGF2BP1 expression was elevated in CRC, increased with tumor stage, and associated with poor survival and proliferative gene signatures. Genetic depletion or pharmacological inhibition of IGF2BP1 impaired cell viability, induced mitotic abnormalities, and promoted apoptosis, whereas its re-expression enhanced tumor formation in vivo. Integrated molecular analyses identified the chromosomal passenger complex (CPC) as a previously unrecognized downstream target of IGF2BP1. IGF2BP1 bound transcripts encoding CPC components and its depletion consistently reduced their expression across multiple cancer cell models. BTYNB disrupted IGF2BP1 association with INCENP, CDCA8, and BIRC5 transcripts and accelerated INCENP mRNA decay. Functionally, INCENP depletion recapitulated the mitotic defects and impaired viability observed upon IGF2BP1 inhibition. Exploiting this mitotic vulnerability, BTYNB synergized with paclitaxel in CRC cell lines and across four independent IGF2BP1-positive patient-derived organoid models. Conclusions Our findings uncover an IGF2BP1-dependent post-transcriptional regulatory mechanism sustaining CPC expression and mitotic integrity in CRC. Targeting this mechanism exposes a therapeutically exploitable mitotic vulnerability and provides a rationale for combining IGF2BP1 inhibition with microtubule-targeting agents.
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BibTeX
@misc{griesler2026targeting,
title = {{Targeting IGF2BP1 Creates a Mitotic Vulnerability in Colorectal Carcinoma}},
author = {B. Griesler and S. Hagemann and R. Winkler and A. Wedler-Geyer and C. Misiak and D. Misiak and A. Rausch and J. Luetzkendorf and T. Mueller and K. U. I. Mir and C. Ihling and F. W. Otto and A. Sinz and J.-H. Klusmann and M. Heuser and L. P. Mueller and N. Bley and S. Huettelmaier},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.761131},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.761131v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeting IGF2BP1 Creates a Mitotic Vulnerability in Colorectal Carcinoma
AU - B. Griesler
AU - S. Hagemann
AU - R. Winkler
AU - A. Wedler-Geyer
AU - C. Misiak
AU - D. Misiak
AU - A. Rausch
AU - J. Luetzkendorf
AU - T. Mueller
AU - K. U. I. Mir
AU - C. Ihling
AU - F. W. Otto
AU - A. Sinz
AU - J.-H. Klusmann
AU - M. Heuser
AU - L. P. Mueller
AU - N. Bley
AU - S. Huettelmaier
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.761131
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.761131v1
AB - Background Mitotic dysregulation is a common feature of colorectal cancer (CRC), yet the contribution of post-transcriptional mechanisms remain incompletely understood. We investigated how the oncofetal RNA-binding protein IGF2BP1 supports mitotic integrity and exposes therapeutic vulnerabilities in CRC. Methods We integrated patient cohort analyses with genetic and pharmacological perturbation of IGF2BP1, transcriptomics, proteomics, RNA-binding assays and functional studies. Xenografts assessed tumor formation, while BTYNB-paclitaxel responses were examined in CRC cell lines and patient-derived organoids. Results IGF2BP1 expression was elevated in CRC, increased with tumor stage, and associated with poor survival and proliferative gene signatures. Genetic depletion or pharmacological inhibition of IGF2BP1 impaired cell viability, induced mitotic abnormalities, and promoted apoptosis, whereas its re-expression enhanced tumor formation in vivo. Integrated molecular analyses identified the chromosomal passenger complex (CPC) as a previously unrecognized downstream target of IGF2BP1. IGF2BP1 bound transcripts encoding CPC components and its depletion consistently reduced their expression across multiple cancer cell models. BTYNB disrupted IGF2BP1 association with INCENP, CDCA8, and BIRC5 transcripts and accelerated INCENP mRNA decay. Functionally, INCENP depletion recapitulated the mitotic defects and impaired viability observed upon IGF2BP1 inhibition. Exploiting this mitotic vulnerability, BTYNB synergized with paclitaxel in CRC cell lines and across four independent IGF2BP1-positive patient-derived organoid models. Conclusions Our findings uncover an IGF2BP1-dependent post-transcriptional regulatory mechanism sustaining CPC expression and mitotic integrity in CRC. Targeting this mechanism exposes a therapeutically exploitable mitotic vulnerability and provides a rationale for combining IGF2BP1 inhibition with microtubule-targeting agents.
ER -