There was an error published in Development 141, 816-829.Edwin W. Rubel was omitted from the authorship of the paper. The correct author list and affiliations appears above.In addition the Acknowledgements and Author contributions sections should read as follows. AcknowledgementsWe thank L. Tong and R. Palmiter (University of Washington) for Pou4f3DTR/+ mice and discussion; S. Baker (St. Jude) for Atoh1-CreERTM mice and discussion; R. Kageyama (Kyoto University) for Hes5-nlsLacZ mice; P. Chambon (Institut Genetique Biologie Moleculaire Cellulaire) for the CreERT2 construct; S. Heller (Stanford University) for the anti-espin antibody and critical reading, J. Corwin, J. Burns and other members of the Corwin laboratory (University of Virginia) as well as members of our laboratories for discussion and critical comments; S. Connell, V. Frohlich, Y. Ouyang and J. Peters (St. Jude) for expertise in confocal imaging; A. Xue, V. Nookala, N.

Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs) mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology and uptake of FM4-64FX dye at adult ages. Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.

A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) with the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies have provided a useful set of resources including disease models suitable to identify and validate potential therapeutic targets in human high-risk hepatoblastoma.

Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and Extra-Terminal domain (BET) proteins are activated in a non-canonical fashion by TGF-β, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX] ). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (p<0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (p<0.001), with associated perturbations in the cell cycle leading to cell cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.

<div>Abstract<p>Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (<i>P</i> < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (<i>P</i> < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.</p></div>