Abstract
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.