Translocating proteins compartment-specifically alter the fate of epithelial-mesenchymal transition in a compartmentalized Boolean network model

Mendik, Péter; Kerestély, Márk; Kamp, Sebestyén; Deritei, Dávid; Kunsic, Nina; Vassy, Zsolt; Csermely, Péter; Veres, Dániel V.

doi:10.1038/s41540-022-00228-7

Cited by 3 publications

References 58 publications

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HHIP’s Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility

Deritei,

Anamika,

Zhou

et al. 2024

Preprint

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A genetic variant near HHIP has been consistently identified as associated with increased risk for Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death worldwide. However HHIP's role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the hedgehog pathway and downstream GLI1 and GLI2 activation. The hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing the wound. Herein, we propose a mechanism to explain HHIP's role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models compiled from the literature, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. We also experimentally test if low HHIP expression is associated with EMT at the edge of wounds by using a scratch assay in a human lung epithelial cell line. Finally, we show evidence supporting our hypothesis in bulk and single cell RNA-Seq data from different COPD cohorts. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema.

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HHIP’s Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility

Deritei,

Anamika,

Zhou

et al. 2024

Preprint

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A multi-level formalism to capture the characteristics of hybrid phenotypes in Epithelial-Mesenchymal Plasticity

Hari,

Tripathi,

Anand

et al. 2024

Preprint

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Epithelial-mesenchymal plasticity (EMP) is a cell-fate switching program that enables cells to adopt a spectrum of phenotypes ranging from epithelial (E) to mesenchymal (M) and hybrid E/M states. Hybrid E/M phenotypes are considered optimal for cancer metastasis due to their association with metastatic initiation and traits such as stemness, drug resistance, and collective migration. Boolean models of gene regulatory networks (GRNs) underlying EMP have provided valuable insights into the dynamics of E and M phenotypes. However, these models fail to capture hybrid phenotypes effectively, as Boolean frameworks allow only binary gene expression, while hybrid E/M cells exhibit partial expression of both E and M genes. To address this limitation, we modified a threshold-based Boolean formalism to incorporate intermediate gene expression levels. The resulting multilevel model reveals new hybrid steady states with partial expression of both E and M genes, expanding the phenotypic landscape beyond that captured by traditional Boolean models. These hybrid states exhibit lower frustration and higher abundance, indicating enhanced stability. By resolving degeneracy in the dynamics, we further demonstrate that hybrid states identified by the multilevel model are more stable. These findings suggest that adding minimal complexity to Boolean models can uncover previously hidden qualitative features of phenotypic landscapes governed by GRNs.

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Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1

Liu,

Yang,

Wang

et al. 2024

Journal of Clinical Investigation

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Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1–increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

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Translocating proteins compartment-specifically alter the fate of epithelial-mesenchymal transition in a compartmentalized Boolean network model

Cited by 3 publications

References 58 publications

HHIP’s Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility

HHIP’s Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility

A multi-level formalism to capture the characteristics of hybrid phenotypes in Epithelial-Mesenchymal Plasticity

Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1

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