Biology subjects

Sodir, N. M.

Publications and source records attributed to Sodir, N. M..

3 recordsLinked to original sources

bioRxiv2026

Myc inhibition triggers GM-CSF-driven regression of pancreatic tumours

The complex aetiology of pancreatic ductal adenocarcinoma (PDAC), together with its desmoplastic and hypoxic microenvironment, hinders effective treatment and contributes to its rapid lethality1. Using a reversibly switchable genetic mouse model that closely recapitulates human PDAC phenotype progression, we previously showed that selective deactivation of oncogenic Myc in PDAC epithelial cells triggers rapid disassembly of advanced PDACs2, both tumor cells and their associated immune microenvironment. Here, leveraging spatiotemporal genomics and multiplex immune profiling we determine the mechanism underpinning this regression programme and identify granulocyte-macrophage colony-stimulating factor (GM-CSF) as its key instructive cytokine, transiently released by pancreatic ductal epithelial cells rapidly following Myc inactivation, that initiates tumour regression. We further demonstrate that type 1 conventional dendritic cells (cDC1s) act as critical effectors in Myc-OFF GM-CSF-driven tumour regression. Both antibody-mediated blockade of GM-CSF and genetic ablation of cDC1s via Batf3 knockout bone marrow transplantation prevent PDAC regression. Conversely, transient systemic administration of recombinant GM-CSF to PDAC-bearing mice promotes rapid cDC1 infiltration and induces marked tumour regression in the sustained presence of Myc activity. Together, these findings reveal that PDAC regression induced by Myc de-activation is mediated by a latent morphogenic programme that is initiated by transient release of GM-CSF from tumour cells. This regression programme is rapid, tissue-specific, involves both neoplastic cells and attendant desmoplastic stroma, is reliant on innate immunity and provides a novel framework for therapeutic intervention in PDAC.

cancer biology↗

bioRxiv2020

Preventing cancer by long-term partial Myc suppression

Myc+/- haploinsufficient mice and mice with deleted Myc enhancers express reduced levels of the pleiotropic transcription factor Myc. Such mice are viable, with relatively mild pathologies, but show delay in onset of certain cancers. However, many phenotypes arising from germline gene perturbation are indirect consequences of adaptive developmental compensation and so do not translate to equivalent phenotypes when applied to adults. To ascertain whether systemic Myc hypomorphism also conferred cancer protection when acutely imposed in adults, and what the side-effects of this might be, we constructed a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will. Acute imposition of Myc hypomorphism in adult mice conferred potent protection against both KRasG12D-driven lung and pancreatic cancers yet elicited only mild haematopoietic side effects. These side effects were completely suppressed by imposing Myc hypomorphism metronomically - a regimen that nonetheless retained potent cancer prophylaxis. Our data identify a key bottleneck at the transition from pre-malignant hyperplasia to overt tumour that is peculiarly reliant on levels of Myc that are higher than those required for most adult physiology, offering a possible window of opportunity for Myc inhibition in cancer prophylaxis.

cancer biology↗

bioRxiv2019

Myc instructs and maintains pancreatic adenocarcinoma phenotype

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its dismal prognosis and its signature fibroinflammatory phenotype. We show that activation of Myc in PanIN epithelial cells is alone sufficient to instruct and maintain immediate transition of indolent PanINs to PDACs phenotypically identical to the spontaneous human disease. Myc does this by inducing a distinct, tissue-specific ensemble of instructive signals that, together, coordinate changes in multiple, stromal and inflammatory cell types to generate the signature PDAC stroma. We also demonstrate that the Myc PDAC switch is completely reversible and that Myc deactivation immediately triggers meticulous disassembly of both PDAC tumor and stroma. Hence, both the formation and deconstruction of the complex PDAC phenotype may be mediated by a single, reversible molecular switch. SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and lacks effective therapies. We show that Myc is a single molecular switch that directly and immediately instructs transition from indolent KRasG12D-induced PanIN to the characteristic complex, multi-cell-type fibroinflammatory and immune-cold PDAC phenotype through the release of a distinct, tissuespecific set of instructive signals. The same combination of KRasG12D and Myc drives a very different phenotype in lung, indicating that the principal phenotypes of adenocarcinomas are dictated by tissue of origin not specific oncogenes. We also show that the Myc switch is immediately and completely reversible: blocking Myc function triggers meticulous disassembly of the entire PDAC tumor-stromal edifice demonstrating that phenotypic complexity is not a barrier to effective treatment of cancers.

cancer biology↗