Biology subjects

Adelaja, A.

Publications and source records attributed to Adelaja, A..

4 recordsLinked to original sources

bioRxiv2026

Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by mutant KRAS, and RAS inhibitors now extend survival in previously treated metastatic disease. Whether treatment shrinks a tumour or only halts its growth depends partly on whether cancer cells die or stop dividing, yet how untreated PDAC cells are balanced between these programmes is unknown. Aims: We aimed to characterise the balance between apoptosis-associated and arrest-associated transcriptional programmes in treatment-naive PDAC and to examine their relationships with tumour subtype, TGM2 expression, tissue organisation, survival and drug sensitivity. Methods and results: We scored 52,999 malignant cells from 18 untreated patients in the Hwang atlas using a transcriptional contrast between genes associated with apoptosis and genes associated with resistance to apoptosis or cell-cycle arrest. In every patient the contrast was shifted toward the arrest-associated side: using equality between the two sides as the dividing threshold, 86.3% of cells with an informative score fell on that side, although the proportion depends on the threshold chosen. The shift recurred in the independent Steele atlas (median 71.6% per sample, range 37.1% to 90.8%). In the discovery cohort, tumours with higher basal-like scores had fewer arrest-side cells, and TGM2 expression was modestly higher on the arrest-associated side in both cohorts. The contrast did not track cell-line drug sensitivity or survival in bulk tumours. Conclusion: Untreated PDAC cells show a reproducible transcriptional bias toward anti-apoptotic and cell-cycle-arrest programmes. Whether this bias predicts cellular responses to treatment remains to be tested.

cancer biology↗

bioRxiv2022

Stimulus-Response signaling dynamics characterize macrophage polarization states

Macrophages show remarkable functional pleiotropy that is dependent on microenvironmental context. Prior studies have characterized how polarizing cytokines alter the transcriptomic and epigenetic landscape. Here we characterized the immune-threat appropriate responses of polarized macrophages by measuring the single-cell signaling dynamics of transcription factor NF{kappa}B. Leveraging a fluorescent protein reporter mouse, primary macrophages were polarized into 6 states and stimulated with 8 different stimuli resulting in a vast dataset. Linear Discriminant Analysis revealed how NF{kappa}B signaling codons compose the immune threat level of stimuli, placing polarization states along a linear continuum between the M1/M2 dichotomy. Machine learning classification revealed losses of stimulus distinguishability with polarization, which reflect a switch from sentinel to more canalized effector functions. However, the stimulus-response dynamics and discrimination patterns did not fit the M1/M2 continuum. Instead, our analysis suggests macrophage functional niches within a multi-dimensional polarization landscape. HighlightsO_LIPolarization of macrophages affects stimulus-response NF{kappa}B dynamics C_LIO_LIFor each condition, NF{kappa}B signaling codons quantify the "immune threat" level C_LIO_LIMachine Learning reveals polarization-induced canalization of stimulus-responses C_LIO_LINF{kappa}B stimulus-responses may define a landscape of macrophage states C_LI eTOC blurbMacrophages are profoundly responsive to their tissue microenvironment, but how that affects their pathogen response functions has not been investigated systematically. Here we studied how their signaling response is affected by six polarizing cytokines. We found each modulates their stimulus-responses highly specifically, producing distinct patterns of stimulus-discrimination. Thereby, these stimulus-response specificities may be used to describe a landscape of functional macrophage states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/485991v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1d34d5forg.highwire.dtl.DTLVardef@17cc0eaorg.highwire.dtl.DTLVardef@15d6022org.highwire.dtl.DTLVardef@1526f72_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats

Acute and chronic inflammatory pathologies involve misregulation of macrophage functions. Physiologically, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NF{kappa}B. The temporal pattern of NF{kappa}B activity determines which genes are expressed, suggesting that a temporal signaling code specifies a stimulus-appropriate immune response. To identify the signaling codewords, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, "oscillatory" trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NF{kappa}B signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NF{kappa}B signaling code for classifying immune threats and demonstrates their biological significance.

immunology↗

bioRxiv2020

NFκB dynamics determine stimulus-responsive epigenomic reprogramming in macrophages

The epigenome defines the cell type, but also shows plasticity that enables cells to tune their gene expression potential to the context of extracellular cues. This is evident in immune sentinel cells such as macrophages, which can respond to pathogens and cytokines with phenotypic shifts that are driven by epigenomic reprogramming1. Recent studies indicate that this reprogramming arises from the activity of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF{kappa}B), which binds not only to available enhancers but may produce de novo enhancers in previously silent areas of the genome2. Here, we show that NF{kappa}B reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NF{kappa}B activity. Testing predictions of a mathematical model of nucleosome interactions, we demonstrate through live cell imaging and genetic perturbations that NF{kappa}B promotes open chromatin and formation of de novo enhancers most strongly when its activity is non-oscillatory. These de novo enhancers result in the activation of additional response genes. Our study demonstrates that the temporal dynamics of NF{kappa}B activity, which encode ligand identity3, can be decoded by the epigenome through de novo enhancer formation. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.

molecular biology↗