PRC2 and MYC repression drives oncofetal reprogramming and autophagy dependence in Colorectal Cancer

The emergence of an oncofetal phenotype in colorectal cancer (CRC) has been linked to therapy resistance and metastatic progression. However, whether this state pre-exists in treatment-naïve tumors or is primarily acquired upon chemotherapy, and the molecular mechanisms underlying these transitions, remain incompletely understood. While transcriptional regulators such as YAP1 and AP1 have been proposed as oncofetal inducers, the epigenetic and metabolic determinants of this process are not fully defined. Here, we integrate transcriptomic analyses from multiple CRC patient cohorts with functional studies in patient-derived organoids (PDOs) to show that both intrinsic and therapy-induced fetal-like CRC states are characterized by coordinated repression of Polycomb Repressive Complex 2 (PRC2) and MYC signaling. This repression involves coordinated downregulation of core and accessory PRC2 components together with attenuation of MYC/MAX activity across patient datasets and experimental models. Functional inhibition of PRC2 is sufficient to unlock fetal and epithelial-to-mesenchymal transition (EMT) transcriptional programs, whereas MYC suppression, mediated in part by MXD1 induction, promotes growth arrest and metabolic adaptation without recapitulating the full fetal signature. Mechanistically, fetal-like CRC cells, irrespective of their origin, display suppression of MYC- and mTOR-driven programs and increased reliance on autophagy. While basal autophagy levels show limited predictive value, induction of fetal-like states by chemotherapy or PRC2 inhibition consistently sensitizes CRC cells to lysosomal blockade. Together, these findings identify PRC2 and MYC repression as convergent regulatory features of oncofetal reprogramming in CRC and reveal autophagy dependence as a context-specific and therapeutically exploitable vulnerability of this aggressive tumor state.