Biology subjects

Takabe, K.

Publications and source records attributed to Takabe, K..

5 recordsLinked to original sources

bioRxiv2026

Tamoxifen and Doxorubicin Synergistically Target Estrogen Receptor beta-Mutant p53-p73 Axis, a Therapeutically Actionable Vulnerability in Triple Negative Breast Cancer

Current therapeutic regimens for triple negative breast cancer (TNBC) are not very effective in majority of patients and have serious adverse effects. Tamoxifen (Tam), a selective estrogen receptor modulator (SERM), routinely used to treat estrogen receptor alpha-positive breast cancer, has traditionally not been considered for TNBC therapy because it lacks expression of ER alpha, the canonical target of Tam. Challenging this conventional clinical paradigm, we have demonstrated, using genetic and pharmacological approaches, that Tam synergizes with DNA-damaging agent doxorubicin (Doxo) to increase cell death by both apoptosis and ferroptosis leading to growth inhibition of TNBC CDXs and PDXs expressing mutant p53. Mechanistically, these responses are dependent on ER beta-mutant p53 interaction enhanced by Tam, thereby disrupting p73-mutant p53 complex resulting in reactivation of p73 and transcriptomic reprogramming converging on apoptosis and ferroptosis. These studies demonstrate the potential for repurposing Tam with Doxo as an effective and safe therapeutic strategy to treat molecularly stratified TNBC.

cancer biology↗

bioRxiv2026

Simultaneous quantification of dynamic bacterial deformation and motility by machine learning

We developed a convolutional neural network-based machine learning technique to simultaneously analyze the morphology and motility of spirochetal bacteria swimming with continuous cellular deformation. Matching probabilities between experimental images and learned models realizes quantification of cell morphology and association with motility. This method can be applied to diverse transformable cells, offering critical biophysical insights into microbial dynamics.

microbiology↗

bioRxiv2026

A novel periplasmic layer formed by an outer membrane lipo-protein governs the cell-envelope integrity and stiffness of Leptospira interrogans

The structural integrity and mechanical properties of the cell envelope are crucial for bacterial physiology and dynamics; however, how specific molecular components govern these properties remains poorly understood. Here, we report the novel structural and mechanical functions of LipL32, the most abundant outer-membrane (OM) lipoprotein in the pathogenic spirochete Leptospira interrogans. LipL32 accounts for approximately 75% of the total OM proteins, yet its functional role has remained enigmatic. Cryo-electron microscopy revealed that the highly dense LipL32 forms a hitherto unappreciated thin layer in the periplasmic space, positioned adjacent to the peptidoglycan (PG) layer. The structural analysis also demonstrates that the disruption of lipL32 by transposon insertion results in irregular deformation of OM and spatial variability in the width of the periplasmic space. Quantitative measurements by optical tweezers confirmed that the lipL32::Tn mutant exhibited a significant reduction in whole-cell stiffness. Consistent with this mechanical impairment, the lipL32::Tn mutant displayed a diminished ability to penetrate a heterogeneous agar mesh model that mimics the hosts extracellular matrix, suggesting an important role for cell rigidity in initial infection via damaged skin. These findings define LipL32 as a critical mechanical stabilizer that maintains the structural integrity of the cell envelope. This work provides a new paradigm for understanding how specialized lipoproteins contribute to bacterial cell mechanics, offering insights into pathogenic invasiveness.

microbiology↗

bioRxiv2021

Exploitation of sulfated glycosaminoglycan status for precision medicine of platinums in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC. SignificanceTNBC is a heterogenous disease, often defined by the absence of a therapeutic target. Our recent results show sGAGs may provide a viable biomarker for Triplatin in patients with TNBC, producing a significant advantage over carboplatin in this setting. Selective precision medicine agents, such as Triplatin, that are active against chemotherapy-resistant disease and exploit molecular biomarkers like sGAGs may significantly benefit patients in this setting.

pharmacology and toxicology↗

bioRxiv2020

Implications of back-and-forth motion and powerful propulsion for spirochetal invasion

The spirochete Leptospira spp. can move in liquid and on a solid surface using two periplasmic flagella (PFs), and its motility is an essential virulence factor for the pathogenic species. Mammals are infected with the spirochete through the wounded dermis, which implies the importance of behaviors on the boundary with such viscoelastic milieu; however, the leptospiral pathogenicity involving motility remains unclear. We used a glass chamber containing a gel area adjoining the leptospiral suspension to resemble host dermis exposed to contaminated water and analyzed the motility of individual cells at the liquid-gel border. Insertion of one end of the cell body to the gel increased switching of the swimming direction. Moreover, the swimming force of Leptospira was also measured by trapping single cells using an optical tweezer. It was found that they can generate [~]17 pN of force, which is [~]30 times of the swimming force of Escherichia coli. The force-speed relationship suggested the load-dependent force enhancement and showed that the power (the work per unit time) for the propulsion is [~]3.1x10-16 W, which is two-order of magnitudes larger than the propulsive power of E. coli. The powerful and efficient propulsion of Leptospira using back-and-forth movements could facilitate their invasion.

microbiology↗