Biology subjects

Wang, M.-T.

Publications and source records attributed to Wang, M.-T..

3 recordsLinked to original sources

bioRxiv2025

CASTOR1: A Novel Tumor Suppressor Linking mTORC1 and KRAS Pathways in Tumorigenesis and Resistance to KRAS-Targeted Therapies in Non-Small Cell Lung Cancer

Cytosolic arginine sensor for mTORC1 Subunit 1 (CASTOR1) functions as a key regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Despite its frequent dysregulation in cancers via mechanisms such as KSHV microRNA-mediated inhibition or AKT-driven phosphorylation and degradation, the impact of CASTOR1 loss on tumor initiation and progression remains poorly understood. Here, we identify CASTOR1 as a critical tumor suppressor in non-small cell lung cancer (NSCLC) by demonstrating that its genetic ablation amplifies tumorigenesis in a KRAS-driven genetically engineered mouse model (GEMM;LSL-KRASG12D). CASTOR1 deficiency markedly enhances lung tumor incidence, accelerates tumor progression, and increases proliferative indices in KRASG12D-driven tumors (KRASG12D;C1KO) compared to CASTOR1 wild type (WT) tumors (KRASG12D;C1WT). Advanced-stage tumors exhibit elevated phosphorylated CASTOR1 (pCASTOR1) and reduced total CASTOR1 levels, suggesting active degradation during tumorigenesis. Mechanistically, CASTOR1 loss amplifies mTORC1 signaling, as evidenced by heightened phosphorylation of downstream effectors 4EBP1 and S6, while also augmenting AKT and ERK activation, uncovering a crosstalk between the PI3K/AKT/mTORC1 and KRAS/ERK pathways. Furthermore, CASTOR1 ablation induces genome instability, which may contribute to enhanced tumor incidence and progression. Importantly, CASTOR1 deficiency confers resistance to KRASG12D-specific inhibitors, while over half of KRASG12D;C1WT tumors also display resistance. Organoids derived from KRASG12D;C1KO and KRASG12D;C1WT tumors reveal a correlation between KRAS inhibitor resistance and hyperactivation of mTORC1, with mTORC1 and PI3K inhibitors sensitizing resistant tumors to KRASG12D-targeted therapies. These findings position CASTOR1 as a novel tumor suppressor that modulates mTORC1 and KRAS signaling to constrain NSCLC progression. Our study further highlights the therapeutic potential of combining mTORC1 or ERK inhibitors with KRAS-targeted therapies for NSCLC characterized by hyperactive KRAS signaling and impaired CASTOR1 activity. HighlightsO_LICASTOR1 functions as a tumor suppressor in NSCLC by limiting KRAS-driven tumor initiation and progression. C_LIO_LICASTOR1 is frequently lost or inactivated in wild-type tumors during tumor progression, contributing to advanced-stage malignancies. C_LIO_LICASTOR1 deficiency amplifies mTORC1 signaling and enhances PI3K/AKT and KRAS/ERK crosstalk, driving tumorigenesis and resistance to KRAS-specific inhibitors. C_LIO_LICombining mTORC1 or PI3K inhibitors with KRAS-targeted therapies effectively overcomes resistance in KRAS-driven NSCLC. C_LI

cancer biology↗

bioRxiv2023

Membrane buckling and the determination of Gaussian curvature modulus

Biological membranes are able to exhibit various morphology due to the fluidity of the lipid molecules within the monolayers. The shape transformation of membranes has been well described by the classical Helfrich theory, which consists only a few phenomenological parameters, including the mean and the Gaussian curvature modulus. Though various methods have been proposed to measure the mean curvature modulus, determination of the Gaussian curvature modulus remains difficult both in experiments and in simulation. In this paper we study the buckling process of a rectangular membrane and a circular membrane subject to compressive stresses and under different boundary conditions. We find that the buckling of a rectangular membrane takes place continuously, while the buckling of a circular membrane can be discontinous depending on the boundary conditions. Furthermore, our results show that the stress-strain relationship of a buckled circular membrane can be used to effectively determine the Gaussian curvature modulus.

biophysics↗

bioRxiv2022

PKC-alpha regulates the phosphorylation of KRAS that suppresses its oncogenic properties

Oncogenic KRAS-driven cancers have long been considered as "undruggable" due to limited therapeutic options. While the recent success of KRAS-G12C inhibitors argues against the "undruggability" of KRAS, this treatment only benefits a small proportion of patients with KRAS mutant cancers, leaving an urgent need for modalities to target other KRAS mutants. KRAS-calmodulin (CaM) signaling axis reportedly regulates the oncogenic properties of KRAS through its C-terminal hypervariable region. Phosphorylation of KRAS by activated protein kinase C (PKC) uncouples KRAS-CaM, resulting in growth inhibition effective against the entire spectrum of KRAS hotspot mutations. However, broadly activating PKC could mediate tumor promoting signaling nodes and cause systemic toxicity, undermining its applicability as an anti-KRAS therapy. Here, we found that prostratin induces KRAS phosphorylation, resulting in an elevated level of active CaM in the cytosol of KRAS mutant cells, and consequentially suppresses their malignancies. A whole-genome wide CRISPR/Cas9 knockout screening, further confirmed by biochemical analysis, revealed that prostratin acts through activating PKC. Functional studies confirmed PKC as the sole kinase to phosphorylate KRAS and, therefore, a KRAS suppressor. Activation of PKC induces senescence in KRAS mutant tumor cells through PTPN14, accompanied by a secretory phenotype contributing to the growth inhibition, and parallelly mediates a nuclear translocation of a CaM-dependent transcription activator, CAMTA-1, which can be a biomarker to indicate the activity of PKC-KRAS-CaM axis. Our findings reveal a previously understudied regulation of KRAS-CaM axis by PKC, which can be an actionable target for developing anti-KRAS therapeutics. One Sentence SummaryThis study deciphers a PKC-led tumor suppressive effect specific to the "undruggable" KRAS-mutant tumor cells through the phosphorylation of KRAS and a consequently altered KRAS-CaM signaling axis.

cancer biology↗