Leveraging WNT Hyperactivation to Kill Colorectal Cancer While Rejuvenating Healthy Intestine.

WNT signaling maintains intestinal homeostasis yet drives colorectal cancer (CRC) when constitutively activated by APC mutations. We overturn the fundamental assumption that APC-mutant tumors exist at maximal WNT activation, revealing instead that cancer cells occupy a precarious "WNT-just-right" zone along a signaling continuum. This discovery exposes an unprecedented therapeutic vulnerability: while normal intestinal epithelium thrives with enhanced WNT signaling, APC-mutant tumor cells undergo apoptosis when pushed beyond their oncogenic setpoint, a phenomenon we term "over-WNTing." Through systematic organoid-based screening, we identified that WNT hyperactivation through multiple approaches: GSK3 inhibition, concentrated WNT proteins, or APC knockdown in GSK3-null backgrounds, selectively kills tumor cells by hyperactivating the driving pathway of CRC. Mechanistically, over-WNTing in APC-mutant cells triggers spillover into non-canonical planar cell polarity signaling, where RHOC upregulation induces ROCK1/2-mediated apoptosis. We demonstrate therapeutic efficacy across the neoplastic continuum, from adenomas to metastatic CRC, including patient-derived tumors, validating GSK3 inhibition with a novel nanoparticle formulation. This discovery enables the first cancer therapy that simultaneously enhances normal tissue function while eliminating tumors. "Over-WNTing" effectively treats adenomas and both mouse and patient-derived CRC, establishing a therapeutic paradigm that exploits fundamental differences in cellular WNT biology to achieve the dual benefit of eliminating cancer while promoting healthy tissue regeneration.