Biology subjects

Shigeta, K.

Publications and source records attributed to Shigeta, K..

3 recordsLinked to original sources

bioRxiv2025

M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors

Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib inhibitor is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives sotorasib resistance by NF-{kappa}B-mediated induction of the epithelial-mesenchymal transition (EMT). Targeting M1C(R)NF-{kappa}B signaling (i) suppresses EMT, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against sotorasib-resistant NSCLC KRAS G12C cell line and patient-derived tumor xenografts. Clinically, targeted treatment of patients with NSCLC KRAS G12C tumors overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.

cancer biology↗

bioRxiv2025

Methylotrophic yeast Candida boidinii enhances the colonization of plant growth-promoting yeast Papiliotrema laurentii in the phyllosphere

Methanol-utilizing microbes are ubiquitous in the phyllosphere, where they assimilate methanol released from pectin, the major component of the plant cell wall. While methylotrophic bacteria Methylobacterium spp. are well studied for their symbiotic relationships with the host plants, the ecology and functional roles of methylotrophic yeasts on plants remain poorly understood. In the effort to isolate yeasts from 26 phyllosphere samples, we identified Candida boidinii as the only methylotrophic yeast, while the remaining isolates, categorized into 17 species in 12 genera, lacked this metabolic trait. To obtain insight into the role of methylotrophic yeasts in the phyllosphere, we investigated the interaction of C. boidinii with a plant growth-promoting yeast (PGPY), Papiliotrema laurentii, one of the identified yeast species during isolation. We found that the colonization of P. laurentii was enhanced by the presence of C. boidinii on Arabidopsis thaliana leaves. Co-cultivation assays revealed that the cell yield of P. laurentii was enhanced by C. boidinii during cultivation on pectin and that the methanol-utilizing ability and pectin methylesterase (PME) activity of C. boidinii contributed to this enhancement. Stable carbon isotope labeling of pectin methylester groups unambiguously confirmed their assimilation by C. boidinii, but not by P. laurentii. These findings suggest that C. boidinii not only survives in the phyllosphere by utilizing pectin-derived methanol but also contributes to the fitness of other yeast species through metabolic cooperation. This study provides new insights into the niche construction and survival strategies of phyllosphere methylotrophic yeasts, highlighting their potential role in shaping microbial community dynamics and promoting beneficial plant-microbe interactions.

microbiology↗

bioRxiv2023

Combined blockade of CXCR4 and PD-1 enhances intratumoral dendritic cell activation and immune responses against HCC

Immune checkpoint inhibitors (ICIs) have transformed systemic therapy for unresectable hepatocellular carcinoma (HCC). Nevertheless, their efficacy is limited to a small percentage of patients, leaving an opportunity for enhancement through synergistic combination therapies. We tested here the combined blockade of programmed death receptor 1 (PD-1) and CXCR4, a receptor for CXCL12 and a key mediator of immunosuppression in the tumor microenvironment in orthotopic grafted and autochthonous models of HCC. We evaluated tumor growth and survival outcomes and examined the underlying mechanisms using immunofluorescence, flow cytometry, RNA-sequencing, and transgenic mice experiments. Combined anti-CXCR4/PD-1 therapy had a robust impact on tumor growth and significantly prolonged survival in all murine preclinical models. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the role of conventional type 1 dendritic cells (cDC1s) in the tumor microenvironment. Moreover, DC reprogramming enhanced anti-cancer immunity by facilitating CD8 T-cell accumulation and activation in the HCC tissue. The effectiveness of the anti-CXCR4 antibody/ICI combination treatment was compromised entirely in Batf3-KO mice deficient in cDC1 cells. Thus, combined ICI therapy with an anti-CXCR4 antibody has the potential to augment the anti-cancer effects and improve survival outcomes in HCC via reprogramming intra-tumoral cDC1 cells.

cancer biology↗