Biology subjects

Evan, G. I.

Publications and source records attributed to Evan, G. I..

3 recordsLinked to original sources

bioRxiv2026

Targeting Myc activates a tissue-specific tumour resolution programme

Neoplastic transformation parallels hallmark cellular programs of tissue regeneration and wound repair1,2. However, the mechanisms driving tumour regression upon oncogenic driver inhibition--and why it often fails--remain poorly understood3-7. Oncogenic KRas mutations and Myc deregulation, two archetypal cancer drivers, frequently occur and cooperate to promote aggressive lung adenocarcinoma (LUAD)8-12. To investigate the mechanistic consequences of targeting Myc in LUAD, we applied spatiotemporally controlled genetic and functional perturbations in a reversible KRas/Myc-driven mouse model, integrated with RNA sequencing and immune protein profiling of tumours and their microenvironment. Acute oncogenic Myc inactivation in epithelial tumour cells elicits a localised regenerative immune response crucially dependent on rapid, transient release of the alarmin cytokine interleukin-33 (IL-33) by alveolar type 2 tumour cells. As a sentinel signal for Myc loss, IL-33 signalling reverses tumour immunosuppression and neoangiogenesis, critically recruits eosinophils, and promotes neoplastic cell elimination, driving regression beyond mere growth arrest. Notably, brief systemic recombinant IL-33 administration to mice with KRas/Myc-driven LUAD induces robust eosinophil influx and near-complete tumour resolution. Together, these findings demonstrate that blocking Myc activates an innate, tissue-intrinsic immune programme rooted in resolution of wound repair and capable of driving regression when activated in a tumour. This opens the possibility of treating cancer not only by blocking mitogenic oncogenic drivers but also by pro-actively triggering pro-resolution pathways.

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↗