Biology subjects

Yakovishina, V.

Publications and source records attributed to Yakovishina, V..

3 recordsLinked to original sources

bioRxiv2026

TFAP2A links drug resistance to antitumor immunity

Combination targeted therapy with BRAF/MEK inhibitors and immune therapy show promising therapeutic outcomes in melanoma; however, the development of drug resistance still represents a formidable challenge. Remaining unexplored is the possibility that BRAF/MEK inhibitors themselves inadvertently compromise the tumor immune microenvironment, limiting the efficacy of immunotherapy when it is used in combination with targeted inhibitors. Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF/MEK drug resistance to antitumor immunity. Specifically, we found that BRAF/MEK inhibitors significantly upregulate TFAP2A. Further, genetic disruption of TFAP2A overcomes BRAF/MEK-inhibitor resistance, promotes stromal enrichment, and enhances intratumoral infiltration of macrophages in an immune-compromised mouse model. In a syngeneic mouse model, TFAP2a knockout not only suppresses tumor growth but also induces potent anti-tumor tertiary lymphoid structures (TLSs). Single cell transcriptomics revealed that the absence of TFAP2A shapes the antitumor microenvironment with an influx of M1-like macrophages, CD8+ T cells and mature dendritic cells. By identifying TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, our work offers a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.

cancer biology↗

bioRxiv2026

Short T1 Fraction as a Marker of Myelin Content: Evidence from Postmortem MRI and Histology

PurposeTo investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth. MethodsMulti-inversion-time MRI data were acquired from four postmortem brain hemisphere specimens from donors with Alzheimers disease on a clinical 3T scanner, and from five dissected tissue blocks containing white matter hyperintensities (WMHs) on a preclinical 3T system. Short-T1 fraction maps were generated using inverse Laplace transform to isolate short-T1 components and were compared with T2-based myelin water imaging metrics through joint T1-T2 correlation analysis. Short-T1 fraction maps from the tissue blocks were further compared with myelin-stained histology. In addition, in vivo short-T1 fraction data were acquired from two elderly volunteers with WMHs to demonstrate translational feasibility. ResultsPostmortem MRI revealed reduced short-T1 fractions in WMHs. T1-T2 correlation analysis showed that the short-T1 fraction was closely associated with the short-T2 (myelin water) component. Strong correlations were observed between short-T1 fractions and optical densities from both Luxol Fast Blue- and myelin basic protein-stained histological sections, supporting the link between the short-T1 signal and myelin content. Consistent findings were also observed in vivo, where significant reductions in short-T1 fractions were detected within WMHs. ConclusionThe short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a clinically translatable biomarker of myelin integrity.

neuroscience↗

bioRxiv2026

MYC-ATF4-ASS1 axis governs intracellular arginine synthesis and dictates the immune microenvironment in melanoma

Drug resistance is a major challenge for both targeted therapies and immunotherapies in cancer. Arginine starvation has proven a promising strategy to overcome recurrent tumors. However, key molecules involved and how immune responses are elicited are not well understood. Here we identify in melanoma cells MYC-ATF4-ASS1 signaling as a pathway, which not only governs intracellular arginine synthesis but also modulates antitumor immunity. ATF4 knockout in melanoma cells phenocopied ASS1 knockout in the same cells, both showing greater sensitivity to arginine depletors such as ADI-PEG20. A combination strategy of BRAF/MEK inhibitors and an arginine depletor shows significant therapeutic effects in a immune-compromised mouse model. Both Atf4 and Ass1 knockout melanomas exhibited enhanced infiltration of Cd8+ T cells and significantly reduced tumor growth in a syngeneic mouse model. Single cell transcriptomics profiled the reshaped tumor microenvironment and revealed that a subset of resident macrophages were reprogrammed by endogenous arginine blockade. Overall, our findings reveal that the MYC-ATF4-ASS1 axis not only controls arginine vulnerability of melanomas but also shapes the immune microenvironment.

cancer biology↗