Biology subjects

Stott, L.

Publications and source records attributed to Stott, L..

3 recordsLinked to original sources

bioRxiv2024

Systems biology-enabled targeting of NF-κB and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-{kappa}B subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry fingerprinting, immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-{kappa}B inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-{kappa}B activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-{kappa}B activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-{kappa}B inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-{kappa}B inhibitors in DLBCL.

cancer biology↗

bioRxiv2024

A novel in-vitro model of the bone marrow microenvironment in AML identifies CD44 and Focal Adhesion Kinase as therapeutic targets to reverse cell adhesion-mediated drug resistance

Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, disruption of the BMME, releasing tumour cells into the peripheral circulation, has therapeutic potential. Using both primary donor AML cells and cell lines, we developed an in-vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistanc E. We identified anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signalling as a contributing factor; adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing adhesion of the most primitive CD34high AML cells in primary autologous co-cultures. Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanised monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.

cancer biology↗

bioRxiv2023

Anthropogenic nest material use correlates with human landscape modifications in a global sample of birds

As humans increasingly modify the natural world, many animals have responded by changing their behaviour. Predicting the extent of these responses is a key step in conserving these species. For example, the tendency for some species of birds to incorporate anthropogenic items - particularly plastic material - into their nests is of increasing concern, as in some cases this behaviour has harmful effects on both adults and young. Studies of this phenomenon, however, have to date been limited in geographic and taxonomic scope. To investigate the global correlates of anthropogenic (including plastic) nest material use, we used Bayesian phylogenetic mixed models and a dataset of recorded nest materials in 6,147 species of birds. We find that after controlling for research effort, anthropogenic nest material use is correlated with proximity to human landscape modification, synanthropic (artificial) nesting locations, breeding environment, and the number of materials that has been recorded within the species nest. We also demonstrate that anthropogenic nest material use is unrelated to body mass, range size, or conservation status. These results indicate that anthropogenic materials are more likely to be included in nests when they are more readily available, as well as potentially by species who have more flexibility in nest material choice.

evolutionary biology↗