Biology subjects

Littlewood, T. D.

Publications and source records attributed to Littlewood, T. D..

3 recordsLinked to original sources

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

Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK

The tyrosine kinase ACK is an oncogene associated with poor prognosis in human cancers. ACK promotes proliferation, in part, by contributing to the activation of Akt, the major PI3-Kinase effector. We show that ACK also regulates PI3-Kinase directly, via interactions with the PI3-Kinase regulatory subunits. ACK interacts with all five regulatory subunit isoforms and directly phosphorylates p85, p85{beta}, p55 and p50 on Tyr607 (or equivalent). Phosphorylation of p85{beta} at this residue promotes cell proliferation but, counterintuitively, ACK does not stimulate PI3-Kinase catalytic activity. We show that ACK stabilizes p85 levels by promoting an interaction between the p85 nSH2 domain and pTyr607, protecting p85 from ubiquitination. We demonstrate that ACK interacts with p85 exclusively in nuclear-enriched cell fractions where the increased levels of the regulatory subunits, together with the nSH2-pTyr607 interaction, promote formation of dimeric p85. We postulate that these novel dimers undertake nuclear functions that contribute to Cdc42-ACK driven oncogenesis. We propose that ACK shapes PI3-Kinase signalling by dampening the PIP3 response, whilst continuing to drive cell proliferation through Akt activation and hereto unexplored but crucial functions of nuclear dimeric p85. These new regulatory subunit dimers represent a previously undescribed mode of regulation for PI3-Kinase and potentially reveal additional avenues for therapeutic intervention.

molecular 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↗