Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

An, Ni; Li, Zhenjie; Yan, Xiaohui; Zhao, Hainan; Yang, Yong; Liu, Ruling; Yang, Yanyong; Gao, Fu; Li, Bailong; Liu, Hu; Yuan, Hongbin

doi:10.1038/s41420-021-00791-8

Cited by 5 publications

(2 citation statements)

References 16 publications

(19 reference statements)

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“…Conversely, inhibiting N-cadherin-based polarization via NSC could decrease such structural integrity, inhibit small metastatic bodies from surviving within the body to re-embed elsewhere [10], and even convert solid tumors and spheroids into disaggregated single cells, as our results demonstrate. Indeed, prior works already demonstrated that NSC treatment effectively decreased the transendothelial migration of prostate cancer cells, suppressed lung tumors, and reduced cancer cell retention in bones [67,68].…”

Section: Discussionmentioning

confidence: 99%

Cadherin-based adhesion regulates mechanical polarization in the actin cortex through Rac1

Lin,

Moazzeni,

Kyker-Snowman

et al. 2023

Preprint

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Tension-adhesion interplay is a crucial mechanism in multicellular organisms that determines the tension differential among internal and external interfaces, which in turn, mediates tissue surface tension and cell sorting, morphogenesis and remodeling, and cancer progression. Cadherins are widely believed to be involved, yet key aspects of the process are neither well characterized nor quantified. This study demonstrates the critical role of N-cadherin in driving mechanical polarization throughout the actin cortical network. N-cadherin regulates both tension increase at the cell-medium (external) interface and decrease at the cell-cell (internal) interface, and their quantitative magnitudes, both absolute and relative, strongly depend on the surface density of N-cadherin. Furthermore, the strength of polarization also increases with respect to the number of cell-cell interfaces for cells within a multicellular cluster. The cadherin-actin contractility linkage is mediated by Rac1, which serves as a molecular switch to trigger cortex remodeling and contraction via myosin II. Inhibition of Rac1 activity decreases polarization and leads to reduced coherence in both small clusters and spheroids. These results provide a pathway to reconcile opposing theories for tissue surface tension generation and perspectives in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Cadherin-based adhesion regulates mechanical polarization in the actin cortex through Rac1

Lin,

Moazzeni,

Kyker-Snowman

et al. 2023

Preprint

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“…For the orthotopic lung cancer model, MSLN-LLC cells suspended in Matrigel were injected into the left lungs of mice [ 38 – 40 ]. On the 7th day post injection, the mice were randomly divided into four groups: PBS, 293-Exo, CAR-Exo, and PTX@CAR-Exo.…”

Section: Methodsmentioning

confidence: 99%

Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

et al. 2023

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Background Non-small cell lung cancer (NSCLC) is a worldwide health threat with high annual morbidity and mortality. Chemotherapeutic drugs such as paclitaxel (PTX) have been widely applied clinically. However, systemic toxicity due to the non-specific circulation of PTX often leads to multi-organ damage, including to the liver and kidney. Thus, it is necessary to develop a novel strategy to enhance the targeted antitumor effects of PTX. Methods Here, we engineered exosomes derived from T cells expressing the chimeric antigen receptor (CAR-Exos), which targeted mesothelin (MSLN)-expressing Lewis lung cancer (MSLN-LLC) through the anti-MSLN single-chain variable fragment (scFv) of CAR-Exos. PTX was encapsulated into CAR-Exos (PTX@CAR-Exos) and administered via inhalation to an orthotopic lung cancer mouse model. Results Inhaled PTX@CAR-Exos accumulated within the tumor area, reduced tumor size, and prolonged survival with little toxicity. In addition, PTX@CAR-Exos reprogrammed the tumor microenvironment and reversed the immunosuppression, which was attributed to infiltrating CD8+ T cells and elevated IFN-γ and TNF-α levels. Conclusions Our study provides a nanovesicle-based delivery platform to promote the efficacy of chemotherapeutic drugs with fewer side effects. This novel strategy may ameliorate the present obstacles to the clinical treatment of lung cancer.

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Mechanisms of radiation‐induced tissue damage and response

Zhou,

Zhu,

Liu

et al. 2024

MedComm

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Radiation‐induced tissue injury (RITI) is the most common complication in clinical tumor radiotherapy. Due to the heterogeneity in the response of different tissues to radiation (IR), radiotherapy will cause different types and degrees of RITI, which greatly limits the clinical application of radiotherapy. Efforts are continuously ongoing to elucidate the molecular mechanism of RITI and develop corresponding prevention and treatment drugs for RITI. Single‐cell sequencing (Sc‐seq) has emerged as a powerful tool in uncovering the molecular mechanisms of RITI and for identifying potential prevention targets by enhancing our understanding of the complex intercellular relationships, facilitating the identification of novel cell phenotypes, and allowing for the assessment of cell heterogeneity and spatiotemporal developmental trajectories. Based on a comprehensive review of the molecular mechanisms of RITI, we analyzed the molecular mechanisms and regulatory networks of different types of RITI in combination with Sc‐seq and summarized the targeted intervention pathways and therapeutic drugs for RITI. Deciphering the diverse mechanisms underlying RITI can shed light on its pathogenesis and unveil new therapeutic avenues to potentially facilitate the repair or regeneration of currently irreversible RITI. Furthermore, we discuss how personalized therapeutic strategies based on Sc‐seq offer clinical promise in mitigating RITI.

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Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

Cited by 5 publications

References 16 publications

Cadherin-based adhesion regulates mechanical polarization in the actin cortex through Rac1

Cadherin-based adhesion regulates mechanical polarization in the actin cortex through Rac1

Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

Mechanisms of radiation‐induced tissue damage and response

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