Pomp, O. | Search bioRxiv

bioRxiv2025

APC loss promotes intestinal transformation through induction of bistable stem cell states

Colorectal cancer (CRC) is a leading cause of cancer deaths, predominantly initiated by genetic inactivation of the APC tumor suppressor. Current dogma holds that APC inactivation promotes tumorigenesis via hyperactivation of the WNT pathway transcriptional effector, {beta}-CATENIN. Although {beta}-CATENIN activation is required for tumor initiation, activating mutations in {beta}-CATENIN are infrequent. Here, we ask what underlies the selective pressure for APC inactivation by comparing the oncogenic effects of APC loss to {beta}-CATENIN hyperactivation. We find that APC loss activates a {beta}-CATENIN-independent fetal intestinal transcriptional program driven by dysregulation of GSK-3 activity upon the LIM-domain protein AJUBA, a positive regulator of YAP. This results in AJUBA stabilization and downstream transcriptional activation of the YAP-driven fetal intestinal gene expression program. We find that {beta}-CATENIN- and YAP-driven transcriptional states are mutually exclusive, existing in an interchangeable bistable balance among APC-null cells. This results in more robust tumor initiation and metastatic progression downstream of APC loss relative to {beta}-CATENIN activation. Taken together, our findings explain the preferential selection for APC inactivation in CRC development and illuminate how {beta}-CATENIN- and YAP-driven gene expression programs coexist to promote tumorigenesis.

cancer biology↗

bioRxiv2023

Targeting mitophagy in SRSF2 mutant hematologic malignancies

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

cancer biology↗