Biology subjects

Ji, h.

Publications and source records attributed to Ji, h..

5 recordsLinked to original sources

bioRxiv2025

Concurrent PIK3CA mutant drives cachexia through inflammatory signaling in EGFR mutant lung cancer

PIK3CA mutation is frequently concurrent with known oncogenic drivers such as EGFR mutation in lung cancer, raising an interesting question about its real function. Cachexia is a systemic disease involving complex interaction between primary tumors and distant organs, significantly contributing to cancer-related mortality. Through integrative study of genetically engineered mouse models (GEMMs) and clinical data, we find concurrent PIK3CA mutant preferentially drives cachexia in EGFR-mutant lung cancer, promoting malignant progression instead of cancer initiation. PIK3CA mutant-mediated cachexia could be overcome by osimertinib (Osi) treatment in Osi-sensitive GEMM. In contrast, chemotherapy, routinely used in clinic for those relapsed from Osi therapy, fails to ameliorate cachexia in Osi-resistant GEMM despite notable tumor suppression. PIK3CA mutant-driven cachexia is mediated through NF-{kappa}B activation and could be dampened by combined aspirin treatment. This work uncovers the biological function of PIK3CA mutant and mechanism behinds its clinical impacts, and proposes a potentially effective strategy for clinical management.

cancer biology↗

bioRxiv2025

Neural circuits between nodose ganglion and pulmonary neuroendocrine cells regulate lung inflammatory responses

The lungs are organs exposed to the external environment, and the air we inhale contains various pathogens, such as endotoxins. The vagus nerve, which innervates the lungs, may play a role in detecting pathogens that invade the lungs. Through transcriptome analysis, tissue clearance imaging, electrical excitability recording, and gene- and cell-specific knockout experiments, we found that vagus nerve endings innervate pulmonary neuroendocrine cells (PNECs). These nerve endings sense bacterial endotoxins via pain receptors (TRPA1) rather than toll-like receptors (TLR4), eliciting electrical excitation and enhancing the production of neuropeptides (CGRP) in the nodose ganglia. In turn, CGRP released by sensory neurons from the nodose ganglia promotes both neuropeptide production and the proliferation of PNECs, thereby amplifying endotoxin-induced lung inflammatory responses. This reveals that the neural circuits between the nodose ganglion and PNECs play a critical role in regulating lung inflammatory responses.

neuroscience↗

bioRxiv2024

Steering cell-state and phenotype transitions by causal disentanglement learning

Understanding and manipulating cell-state and phenotype transitions is essential for advancing biological research and therapeutic treatment. We introduce CauFinder, an advanced framework designed to accurately identify causal regulators of these transitions and further precisely steer such transitions by integrating causal disentanglement modelling with network control based solely on observed data. By leveraging do-calculus and optimizing information flow metrics, CauFinder can distinguish causal factors from spurious ones, ensuring precise control over desired state transitions. One significant advantage of CauFinder is its ability to identify those variables causally affecting the cell-state/phenotype transitions among all observed variables, both theoretically and computationally, leading to the identification of their master regulators when combined with network control. Consequently, by employing a counterfactual algorithm, CauFinder is able effectively to facilitate desirable state transitions or steer these transitional trajectories/paths by modulating these causal drivers. Beyond its theoretical advantages, CauFinder outperforms existing approaches computationally in both simulated and real-world settings. CauFinder is able to not only reveal natural biological transition processes such as (a) cell differentiation, (b) lung adenocarcinoma (LUAD) to lung squamous cell carcinoma (LUSC) transdifferentiation and (c) drug-sensitive to drug-resistant transitions but also identify the causal regulators of their reverse transition processes, such as (A) cell dedifferentiation, (B) LUSC to LUAD transdifferentiation and (C) drug-resistant to drug-sensitive transitions. These findings highlight its superior ability to causally uncover essential regulatory mechanisms and accurately steer cell-state/phenotype transitions, thus providing novel therapeutic strategies.

bioinformatics↗

bioRxiv2023

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1-mutant lung cancer

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+ degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)--key downstream effectors of LKB1-- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCELoss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

cancer biology↗

bioRxiv2021

Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis

Small cell lung cancer (SCLC) is a recalcitrant cancer featured with high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using Rb1L/L/Trp53L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as SCLC metastasizing cell (SMC), which is progressively transitioned from non-metastasizing NCAMloCD44hi cell (Non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal an important role of SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-Non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

cancer biology↗