Biology subjects

Ju, Z.

Publications and source records attributed to Ju, Z..

8 recordsLinked to original sources

bioRxiv2025

BRAFV600E-Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling

Secretion of ligands of the human epidermal growth factor (EGFR) family of receptors or erythroblastic leukemia viral oncogene family (ERBB1-4) is a feature common to many cancer cells. However, our understanding of the role of autocrine ligands in the aberrant behavior of cancer remains incomplete. Here we demonstrate that, in numerous preclinical models of lung tumorigenesis, BRAFV600E signaling promotes expression of ligands including HB-EGF, TGF, Epi- and Amphiregulin. Moreover, using both genetic or pharmacological approaches, we demonstrate that ligand-mediated activation of EGFR signaling in the tumor cell is required to sustain both early-stage BRAFV600E-driven lung tumorigenesis and supports late-stage BRAFV600E-driven lung cancer maintenance. Unbiased Reverse Phase Protein Analyses (RPPA) analyses, paired with targeted validation, reveals ERBB signaling serves to sustain signaling through the ERK1/2 MAP kinase pathway, through effects on ARAF and CRAF, and on the parallel JUN kinase (JNK) pathway. Furthermore, EGFR is activated in a cohort of BRAF-mutated lung cancer patients both pre- and post-treatment. Finally, we noted significant improvement in the depth and durability of therapeutic responses in preclinical models of BRAFV600E-driven lung cancer by combined inhibition of both BRAFV600E signaling plus pan-ERBB signaling. Collectively, this work provides evidence for an important role for ERBB family signaling in the genesis and maintenance of BRAFV600E-driven lung cancers, and the potential for future therapeutic improvement by rational combination targeting of these pathways. SIGNIFICANCEBRAFT1799A serves as a predictive biomarker for FDA-approved targeted inhibition of BRAFV600E oncoprotein kinase signaling in non-small cell lung cancer (NSCLC). However the occurrence of primary or acquired drug resistance limit the depth and durability of patient responses. Studies described here provide a mechanistic rationale for clinical testing of first-line BRAFV600E inhibition combined with pan-ERBB inhibition to improve the depth and durability of initial patient responses, and delay the emergence of lethal drug resistant disease.

cancer biology↗

bioRxiv2024

An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer

T cells are generally sparse in hormone receptor-positive (HR+) breast cancer, potentially due to limited antigen presentation, but the driving mechanisms of low T cell abundance remains unclear. Therefore, we defined and investigated programs ( gene modules), related to estrogen receptor signaling (ERS) and immune signaling using bulk and single-cell transcriptome and multiplexed immunofluorescence of breast cancer tissues from multiple clinical sources and human cell lines. The ERS gene module, dominantly expressed in cancer cells, was negatively associated with immune-related gene modules TNF/NF-{kappa}B signaling and type-I interferon (IFN-I) response, which were expressed in distinct stromal and immune cell types, but also, in part, expressed and preserved as a cancer cell-intrinsic mechanisms. Spatial analysis revealed that ERS strongly correlated with reduced T cell infiltration, potentially due to its association with suppression of TNF/NF-{kappa}B-induced angiogenesis and IFN-I-induced HLA expression in macrophages. Preoperative endocrine therapy in ER+/HER2-breast cancer patients produced better responses in ERS-high patients, with TNF/NF-{kappa}B expression associated with reduced ERS. Targeting these pathways may enhance T cell infiltration in HR+ breast cancer patients. Statement of SignificanceThis study elucidates the immunosuppressive role of ER signaling in breast cancer, highlighting a complex interplay between cancer, stromal, and immune cells and reveals potential approaches to enhance immunogenicity in HR+ breast cancer. These findings offer crucial insights into immune evasion in breast cancer and identify strategies to enhance T cell abundance.

cancer biology↗

bioRxiv2024

Exploring Pathogenic Mutation in Allosteric Proteins: the Prediction and Beyond

Allosteric regulation that triggers the functional activity of a protein through conformational changes is an inherent function of the protein in numerous physiological and pathological scenarios. In the post-genomic era, a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiation and progression of diseases. Here, we analyzed more than 38539 mutations observed in 90 human genes with 740 allosteric protein chains. We found that existing allosteric protein mutations are associated with many diseases, but the clinical significance of the majority of mutations in allosteric proteins remains unclear. Next, we developed a machine-learning-based model for pathogenic mutation prediction of allosteric proteins based on the intrinsic characteristics of proteins and the prediction results from existed methods. When tested on the benchmark allosteric protein dataset, the proposed method achieves AUCs of 0.868 and AUPR of 0.894 on allosteric proteins. Furthermore, we explored the performance of existing methods in predicting the pathogenicity of mutations at allosteric sites and identified potential significant pathogenic mutations at allosteric sites using the proposed method. In summary, these findings illuminate the significance of allosteric mutation in disease processes, and contribute a valuable tool for the identification of pathogenic mutations as well as previously unknown disease-causing allosteric-protein-encoded genes.

bioinformatics↗

bioRxiv2022

Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

Cardiovascular disease is the leading cause of death worldwide due to the inability of adult heart to regenerate after injury. N6-methyladenosine (m6A) methylation catalyzed by the enzyme methyltransferase-like 3 (Mettl3) plays important roles in various physiological and pathological bioprocesses. However, the role of m6A in heart regeneration remains largely unclear. To study m6A function in heart regeneration, we modulated Mettl3 expression in vitro and in vivo. Knockdown of Mettl3 significantly increased the proliferation of cardiomyocytes and accelerated heart regeneration following heart injury in neonatal and adult mice. However, Mettl3 overexpression decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice. Conjoint analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq identified Fgf16 as a downstream target of Mettl3-mediated m6A modification during postnatal heart regeneration. RIP-qPCR and luciferase reporter assays revealed that Mettl3 negatively regulates Fgf16 mRNA expression in an m6A-Ythdf2-dependent manner. The silencing of Fgf16 suppressed the proliferation of cardiomyocytes. However, the overexpression of {Delta}Fgf16, in which the m6A consensus sequence was mutated, significantly increased cardiomyocyte proliferation and accelerated heart regeneration in postnatal mice compared with wild-type Fgf16. Our data demonstrate that Mettl3 post-transcriptionally reduces Fgf16 mRNA levels through an m6A-Ythdf2-dependen pathway, thereby controlling cardiomyocyte proliferation and heart regeneration.

cell biology↗

bioRxiv2021

Unraveling the Connections between Calreticulin and Myeloproliferative Neoplasms via Calcium Signalling

Mutations in the form of insertions and deletions (INDEL) in the calreticulin gene lead to essential thrombocythemia which is characterized by the formation of thrombosis. However, the connection between calreticulin INDEL and essential thrombocythemia remains largely elusive. Through combined molecular dynamics simulation and in-vitro studies on the wild type and mutated isoforms of calreticulin, the mechanism underlying the calreticulin INDEL induced essential thrombocythemia was investigated at the molecular level. Our results demonstrate that mutations in exon-9 could lead to significant conformational variations of calreticulin structure and thereby reducing its interaction with calcium ions due to decreased electrostatic contributions. The consequence of mutations on calreticulins structural integrity was revealed by identifying the key residues and their roles in calcium binding. Furthermore, mutations implemented by CRISPR-Cas9 in exon-9 showed diminished calcium signaling in HEK-293T cells, which agree well with our in-silico findings. The current study might help in understanding of the interactions between calreticulin exon-9 INDEL and calcium ions mediated by the structural variations of calreticulin. The results provide useful information for designing novel therapeutic approaches targeting essential thrombocythemia.

cancer biology↗

bioRxiv2020

Large-scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines

Perturbation biology is a powerful approach to developing quantitative models of cellular behaviors and gaining mechanistic insights into disease development. In recent years, large-scale resources for phenotypic and mRNA responses of cancer cell lines to perturbations have been generated. However, similar large-scale protein response resources are not available, resulting in a critical knowledge gap for elucidating oncogenic mechanisms and developing effective cancer therapies. Here we generated and compiled perturbed expression profiles of ~210 clinically relevant proteins in >12,000 cancer cell-line samples in response to >150 drug compounds using reverse-phase protein arrays. We show that integrating protein response signals substantially increases the predictive power for drug sensitivity and aids in gaining insights into mechanisms of drug resistance. We build a systematic map of protein-drug connectivity and develop an open-access, user-friendly data portal for community use. Our study provides a valuable information resource for a broad range of quantitative modeling and biomedical applications. HighlightsO_LIA large collection of cancer cell line protein responses to drug perturbations C_LIO_LIPerturbed protein responses greatly increase predictive power for drug sensitivity C_LIO_LIBuild a systematic map of protein-drug connectivity based on response profiles C_LIO_LIDevelop a user-friendly, interactive data portal for community use C_LI

systems biology↗

bioRxiv2019

Spatial distribution of lamin A determines nuclear stiffness and stress-mediated deformation

The nucleus is the largest organelle and information center of the cell; while diverse cellular components have been identified as mechanotransduction elements, the deformation of the nucleus itself is emerging as a critical mechanosensory mechanism, suggesting that the nuclear stiffness is essential in determining responses to intracellular and extracellular stresses. The nuclear membrane protein, lamin A, is known to be a dominant component in nuclear stiffening; however, the quantitative relationship between lamin A expression and nuclear deformation is still unclear. Here we measure the nuclear moduli as a function of lamin A expression and applied stress, revealing a linear dependence of bulk modulus on lamin A expression. We also find that the bulk modulus is anisotropic, with the vertical axis of the nucleus being more compliant than the minor and major axis. To examine how lamin A influences nuclear mechanics at the sub-micron scale we correlated the spatial distribution of lamin A with 3D nuclear envelope deformation, revealing that local areas of the nuclear envelope with higher expression levels of lamin A have correspondingly lower local deformations, and that increased lamin A expression levels result in a narrower distribution of smaller deformations. These findings describe the complex dispersion of nuclear deformations as a function of lamin A expression and distribution and implicate a role in mechanotransduction.

bioengineering↗

bioRxiv2018

PARPi triggers STING-dependent immune response and enhances therapeutic efficacy of immune checkpoint blockade independent of BRCAness

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPis are believed to exert their therapeutic effects mainly through the blockade of single-strand DNA damage repair, which leads to the accumulation of toxic DNA double strand breaks, specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here, we show that PARPis modulate immune reposes, which contribute to their therapeutic effects independent of BRCA1/2 mutations. The mechanism underlying this PARPi-induced reprogramming of anti-tumor microenvironment involves a promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions. This in turn activates the DNA sensing cGAS-STING pathway and stimulates production of type I interferons. Ultimately, these events promote PARPi-induced antitumor immunity independent of BRCAness, which can be further enhanced by immune checkpoint blockade. Our results may provide a mechanistic rationale for using PARPis as immunomodulatory agents to harness therapeutic efficacy of immune checkpoint blockade.

cancer biology↗