Biology subjects

Feng, W. W.

Publications and source records attributed to Feng, W. W..

5 recordsLinked to original sources

bioRxiv2026

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

cancer biology↗

bioRxiv2025

Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UECs). Here, in cellular models and primary human tumors, we find that ARID1A/B deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Further, treatment with clinical-grade SMARCA4/2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UEC and other cBAF-disrupted cancer types.

molecular biology↗

bioRxiv2024

Construction of Animal Models Based on Exploring Pathological Features and Mechanisms of Different Locations in the Progression of DVT-APTE-CTEPD/CTEPH

BackgroundChronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH) are sequelae of acute pulmonary embolism (APE) and severely affect patients health and quality of life. The treatment of these conditions is challenging, and their underlying mechanisms remain unclear. The main reason for this is the lack of an animal model that can fully simulate the entire chain of DVT-APTE-CTEPD/CTEPH progression. The objective of this study is to construct an ideal animal model that simulates the major pathological changes of DVT-APTE-CTEPD/CTEPH and can be used for mechanistic exploration. We aim to compare the advantages and disadvantages of different modeling approaches and provide an experimental basis for investigating the mechanisms of pulmonary embolism chronicization at different stages of evolution. Methods and MaterialsWe first evaluated the pathological changes in the pulmonary arterial intima stripping tissue of CTEPH patients. Animal models were established by multiple injections of thrombus columns through the internal jugular vein to simulate distal remodeling of the pulmonary artery. To simulate significant remodeling and fibrosis in the middle and distal segments of the pulmonary artery, thrombus columns were injected along with splenectomy. A CTEPD model with intimal fibrosis remodeling was successfully established by selectively injecting large thromboemboli into the pulmonary artery sites in large animals (dogs). A rat model with pathological manifestations of intimal fibrosis remodeling in the proximal end of the pulmonary artery was constructed using large thrombi combined with nitric oxide synthase inhibitors. An animal model of DVT was established using the inferior vena cava ligation method. ResultsAccording to the different pathological features and mechanisms observed in the progression of human DVT-APTE-CTEPD/CTEPH, we constructed animal models that conform to these pathological manifestations and mechanisms, each with its own advantages. Furthermore, the different methods used to construct animal models can be integrated and applied together. ConclusionAnimal models constructed using different modeling methods can effectively simulate the pathological and physiological manifestations of the corresponding stages of chronic pulmonary embolism. Researchers can select the aforementioned models according to their specific research purposes, directions, and requirements.

zoology↗

bioRxiv2023

Parsing digital or analogue TCR performance through piconewton forces

{beta} T-cell receptors (TCRs) recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374 /Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker upregulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies. One Sentence SummaryQuality of ligand recognition in a T-cell repertoire is revealed through application of physical load on clonal T-cell receptor (TCR)-pMHC bonds

immunology↗

bioRxiv2023

Transferrin Receptor Targeting Chimeras (TransTACs) for Membrane Protein Degradation

Cancer cells require high levels of iron for rapid proliferation, leading to a significant upregulation of the iron carrier protein Transferrin Receptor (TfR) on their cell surface. Leveraging this phenomenon and the exceptionally fast endocytosis rate of TfR, we introduce Transferrin Receptor TArgeting Chimeras (TransTAC), a novel molecular archetype for membrane protein degradation in cancers and other cell types. TransTACs repurpose the naturally recycling receptor TfR1 for protein degradation. To accomplish this, we utilized a combination of protein engineering strategies to redirect the target protein from recycling-endosome trafficking to lysosomal degradation. We show that TransTACs can highly efficiently degrade a diverse range of single-pass, multi-pass, native, or synthetic membrane proteins, establishing new possibilities for targeted cancer therapy.

bioengineering↗