Biology subjects

Law, S.

Publications and source records attributed to Law, S..

4 recordsLinked to original sources

bioRxiv2026

Disrupting Myeloid Persistence and Replenishment Enables Sustained Control of Esophageal Squamous Cell Carcinoma

Responses to macrophage-directed therapy can be transient because tumors preserve myeloid support through complementary persistence and replenishment. In esophageal squamous cell carcinoma (ESCC), CSF1R inhibition reduced established tumor-associated macrophages but was followed by expansion of Ly6C/CCR2-positive monocytic and Ly6G-positive granulocytic populations. Low-dose decitabine preferentially restricted recruited populations while sparing a LYVE1-associated macrophage state, exposing reciprocal pharmacologic blind spots. Combined treatment suppressed both arms and produced sustained control across patient-derived organoid xenograft, orthotopic, and immunocompetent models. Neutrophil depletion reproduced initial regression but not sustained control, indicating that the recruited escape arm extended beyond Ly6G-positive granulocytes. Single-cell profiling mapped these vulnerabilities onto a treatment-resolved myeloid architecture comprising a C1qa-positive TAM continuum, a C1qa-negative Ccr2/Ly6c2-high inflammatory monocytic-like compartment, and a LYVE1/MRC1-positive tissue-supportive macrophage state. Human ESCC contained corresponding macrophage programs and an adverse-outcome-associated LYVE1-rich niche. These findings identify state-aware coverage of complementary myeloid vulnerabilities as a strategy to overcome escape from macrophage-directed therapy.

cancer biology↗

bioRxiv2026

Trained phages constrain evolutionary routes to antibiotic resistance in Escherichia coli

Bacteriophages are major drivers of bacterial evolution and can impose strong selection on traits that mediate resistance and fitness. This creates the possibility of using phage to steer microbial adaptation toward predictable phenotypic outcomes. Yet bacterial populations often evolve phage resistance through diverse genetic routes, not all of which impose meaningful costs or trade-offs. Such evolutionary flexibility can allow bacteria to escape phage selection without acquiring the desired phenotype, limiting the reliability of phage-based evolutionary steering. Here, we develop a directed phage evolution strategy that eliminates cost-free resistance pathways, forcing bacteria into evolutionary trajectories that restore antibiotic susceptibility. We isolated two novel Microviridae phages (BLS2 and BLS5) that infect E. coli BL21 and found that bacteria evolved resistance through two distinct mechanisms: mutations in lipopolysaccharide (LPS) biosynthesis genes, which carried substantial fitness costs and conferred sensitivity to erythromycin, and loss-of-function mutations in yajC, which imposed no fitness penalty and maintained full antibiotic resistance. We show that YajC is a previously uncharacterised accessory receptor required for phage genome translocation across the inner membrane. We then used this mechanistic understanding to design a phage training regime that evolved phages capable of infecting yajC mutants, thereby closing this cost-free escape route. Bacteria challenged with trained phages were constrained to evolve LPS-based resistance, and were consequently resensitised to erythromycin. Our results demonstrate that directed phage evolution can reshape the fitness landscape of bacterial resistance, channelling adaptation along trajectories that carry predictable phenotypic costs - with broad implications for phage-mediated manipulation of microbial populations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/742405v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@14b387aorg.highwire.dtl.DTLVardef@168ff62org.highwire.dtl.DTLVardef@56a8c9org.highwire.dtl.DTLVardef@16363e5_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2024

ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma

Tumor protein p63 isoform {Delta}Np63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of {Delta}Np63 in ESCC. We showed that {Delta}Np63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell {Delta}Np63-IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of {Delta}Np63 resulted in reduced cell viability. {Delta}Np63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. {Delta}Np63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with {Delta}Np63 were also observed in lung SCC. These results support the potential application of {Delta}Np63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

cancer biology↗

bioRxiv2019

Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties

Transplantation of Olfactory Ensheathing Cells (OECs) is a potential therapy for the regeneration of damaged neurons. While they maintain tissue homeostasis in the olfactory mucosa (OM) and olfactory bulb (OB), their regenerative properties also support the normal sense of smell by enabling continual turnover and axonal regrowth of olfactory sensory neurons (OSNs). However, the molecular physiology of OECs is not fully understood, especially that of OECs from the mucosa. Here, we carried out whole-cell patch clamp recordings from individual OECs cultured from the OM and OB of the adult rat, and from the human OM. A subset of OECs from the rat OM cultured 1-3 days in vitro (DIV) had large weakly rectifying K+ currents, which were sensitive to Ba2+ and desipramine, blockers of Kir4-family channels. Kir4.1 immunofluorescence was detectable in OM cells co-labelled for the OEC marker S100, and found adjacent to axons of OSNs. OECs cultured from rat OB had distinct properties though, displaying strongly rectifying inward currents at hyperpolarized membrane potentials and strongly rectifying outward currents at depolarized potentials. Kir4.1 immunofluorescence was not evident in OECs adjacent to axons of OSNs in the OB. A subset of human OECs cultured from the OM of adults had membrane properties comparable to those of the rat OM, i.e. dominated by Ba2+-sensitive weak inwardly rectifying currents. The membrane properties of peripheral OECs are different to those in central OECs, suggesting they may play distinct roles during olfaction.\n\nTable of Contents Image\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC=\"FIGDIR/small/640839v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (39K):\norg.highwire.dtl.DTLVardef@7bc4edorg.highwire.dtl.DTLVardef@1bdc7c1org.highwire.dtl.DTLVardef@85851corg.highwire.dtl.DTLVardef@1e620b8_HPS_FORMAT_FIGEXP M_FIG C_FIG Main pointsO_LIPeripheral and central OECs are functionally distinct\nC_LIO_LIPeripheral OECs have large weak inward rectifier currents\nC_LIO_LICentral OECs have strong inward and outward rectifier currents\nC_LI

physiology↗