Biology subjects

Bykov, A.

Publications and source records attributed to Bykov, A..

3 recordsLinked to original sources

bioRxiv2024

YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1 mediated reprogramming of bone mesenchymal stem cells

AbstractEwing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatments. Insulin like growth factor (IGF) 1 was previously reported an autocrine growth factor for EwS, but only 10% of patients responded to IGF-1 receptor blockade. Although presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a conditional mouse model did not result in tumor formation but led to skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprogrammed limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identified a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reversed the transformed phenotype of EWS::FLI1 expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/603565v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@a6a298org.highwire.dtl.DTLVardef@1fcab8aorg.highwire.dtl.DTLVardef@1621e27org.highwire.dtl.DTLVardef@a9994e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Beyond Life: Exploring Hemodynamic Patterns in Postmortem Mice Brains

We use Laser Speckle Contrast Imaging (LSCI) for transcranial visualization of cerebral blood flow microcirculation in mice during and after cardiac arrest. Analyzing time series of LSCI images, we observed temporal variations in blood flow distribution across the brain surface for up to several hours postmortem. Utilizing Fast Fourier Transform (FFT) analysis, we depicted the decay in blood flow oscillations and microcirculation following death. Due to the exponential drop in blood flow intensity and ensuing non-stationary conditions, Continuous Wavelet Transform (CWT) was applied to identify potential spatial or temporal synchronization patterns in cerebral hemodynamics. Additionally, we conducted Non-negative Matrix Factorization (NMF) analysis with four components to segment LSCI images, revealing temporal alterations in structural subcomponents. This integrated approach, combining LSCI, FFT, CWT and NMF, provides a comprehensive tool for understanding cerebral blood flow dynamics in mice, metaphorically capturing the end of the tunnel experience. Results indicated a primary localization of hemodynamic activity in the olfactory bulbs postmortem, followed by minor successive relocations of blood microflows between the somatosensory and visual cortical regions via the superior sagittal sinus. The proposed approach opens avenues for further exploration into these phenomena, potentially bridging the gap between neuroscientific understanding and the longstanding mysteries surrounding consciousness and perception at the end of life.

bioengineering↗

bioRxiv2023

NK cells shape the clonal evolution of B-ALL cells by IFN-γ production

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+ B acute lymphoblastic leukaemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Whereas most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumour cell clones, which were characterised by an IFN-{gamma} signature. Besides well-known regulators of immune evasion, our analysis of NK cell resistant tumour cells revealed the upregulation of genes, including Ly6a, which we found to promote NK cell resistance in leukaemic cells. Translation of our findings to the human system showed that high expression of LY6E on tumour cells impaired the physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.

cancer biology↗