Biology subjects

Takenaka, T.

Publications and source records attributed to Takenaka, T..

5 recordsLinked to original sources

bioRxiv2026

M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS

IntroductionThe RAS(ON) multi-selective daraxonrasib (RMC-6236) inhibitor is effective in patients with NSCLC KRAS mutant cancers. Tolerance to daraxonrasib invariably develops by mechanisms that remain unclear. There is no known involvement of the M1C oncogenic protein in daraxonrasib resistance. MethodsNSCLC H358 KRAS(G12C), H2122 KRAS(G12C) and patient derived MGH1112 KRAS(G12C) cells with acquired daraxonrasib resistance were investigated for M1C dependence in studies of SHP2, STAT1/3 and NF-KB activation, clonogenicity, and self-renewal capacity. ResultsWe demonstrate that M1C is induced as a protective response in NSCLC KRAS(G12C) mutant cells treated with daraxonrasib. We report that M1C forms novel cell membrane-associated biomolecular condensates with the SHP2 protein tyrosine phosphatase in driving daraxonrasib resistance. M1C integrates SHP2 activation with induction of (i) oncostatin-m/gp130/STAT3 signaling, and (ii) the NF-{kappa}B-mediated epithelial-mesenchymal transition (EMT) pathway. The functional significance of this M1C-driven pathway is supported by the demonstration that targeting STAT3 and NF-{kappa}B reverses daraxonrasib resistance. Consistent with M1C dependence, we also show that targeting M1C is effective against daraxonrasib-resistant NSCLC KRAS mutant cell line and tumor models. In contrast, M1C drives sotorasib resistance by STAT1-mediated inflammatory signaling, demonstrating that M1C confers resistance to KRAS(G12C)-selective and RAS(ON) tri-complex inhibitors by noncongruent mechanisms. ConclusionsThese findings demonstrate that M1C is required for daraxonrasib tolerance and is a potential target for the treatment of patients with NSCLC KRAS(G12C) mutant tumors refractory to this agent.

Cancer Biology↗

bioRxiv2026

Trajectory inference of epithelial-centered neighborhood profiles reconstructs a pseudo-temporal continuum in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by complex lung architecture and spatially heterogeneous remodeling, which have hindered integrated analysis of cell-intrinsic activity and intercellular communication during disease progression. Here we profiled six IPF lung specimens comprising more than 630,000 cells using the Xenium 5k panel and developed an epithelial-centered neighborhood profiling framework based on the local cellular composition around each epithelial cell. This approach captured fibrosis-associated variation in epithelial niches without requiring predefined histological regions. Pseudo-temporal continuum inference of these profiles reconstructed a continuous axis that reflected the spatial progression of fibrotic remodeling from relatively preserved alveolar regions to fibrotic and airway-like remodeled regions. Within this spatial dataset, we mapped coordinated changes in epithelial states, local microenvironments, epithelial intracellular pathway activities, and directional interactions with neighboring cell types along the same axis. Our findings provide a spatial framework that generates testable hypotheses for progressive epithelial niche remodeling in IPF.

bioinformatics↗

bioRxiv2026

Sequential restriction of SNARE-mediated fusion by the COPII inner coat and SNARE chaperones

SNARE-mediated fusion requires assembly of four SNARE domains (R, Qa, Qb, and Qc) distributed across two membranes, with an SM (Sec1/Munc-18 family) chaperone catalyzing this assembly. We investigated topological requirements for the four SNAREs that mediate ER-Golgi fusion using in vitro assays. In the presence of the cognate SM Sly1, we find that a single topology drives efficient fusion: the R SNARE on one membrane versus Qa/Qb/Qc SNAREs on the other. These results prompted us to look upstream, at COPII-SNARE interactions. The assembled COPII coat is known to block fusion. We discovered that of five COPII core subunits, the Sar1 GTPase and Sec23/Sec24 subunits were necessary and sufficient to prevent fusion for prolonged periods, and that Sar1 was dispensable for inhibition over short periods. When Sec24- interactions with vesicle SNAREs were disrupted, inhibition was relieved, indicating that SNARE sequestration by COPII prevents fusion. These observations help to explain how appropriate fusion events are facilitated while inappropriate events are deterred.

cell biology↗

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↗

bioRxiv2020

Gatekeeper helix activates Golgi SM protein Sly1 and directly mediates close-range vesicle tethering

The essential Golgi protein Sly1 is a member of the SM (Sec1/mammalian Unc-18) family of SNARE chaperones. Sly1 was originally identified through gain-of-function alleles that bypass requirements for diverse vesicle tethering factors. Employing genetic analyses and chemically defined reconstitutions of ER-Golgi fusion, we discovered that a loop conserved among Sly1 family members is not only autoinhibitory, but also acts as a positive effector. An amphipathic helix within the loop directly binds high-curvature membranes; membrane binding is required for relief of Sly1 autoinhibition and allows Sly1 to directly tether incoming vesicles to the Qa-SNARE on the target organelle. The SLY1-20 allele bypasses requirements for diverse tethering factors but loses this functionality if Sly1 membrane binding is impaired. We propose that long-range tethers, including Golgins and multisubunit tethering complexes, hand off vesicles to Sly1, which then tethers at close range to activate SNARE assembly and fusion in the early secretory pathway.

cell biology↗