p53 governs an AT1 differentiation programme in lung cancer suppression

Kaiser, Alyssa M.; Gatto, Alberto; Hanson, Kathryn J.; Zhao, Richard; Raj, Nitin; Ozawa, Michael G.; Seoane, José A.; Bieging-Rolett, Kathryn; Wang, Mengxiong; Li, Irene; Trope, Winston; Liou, Douglas Z.; Shrager, Joseph B.; Plevritis, Sylvia K.; Newman, Aaron M.; Rechem, Capucine Van; Attardi, Laura D.

doi:10.1038/s41586-023-06253-8

Cited by 17 publications

(10 citation statements)

References 73 publications

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“…This process occurs at very low rates during homeostasis, with an approximate turnover rate of 0.005% of the alveolar surface with new AT2 cell-derived AT1 cells per day (30). Several signaling pathways have been implicated as regulators of AT2 cell transdifferentiation, including Wnt/β-catenin, BMP, TGF-β, and p53 (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…Mice with loss of function of both Sin3a and p53 did not exhibit AT2 cell loss and did not develop significant fibrosis, indicating that activation of the p53 pathway is necessary to induce AT2 cell senescence and fibrosis (24). While some reports suggest that p53 is necessary for complete AT2-to-AT1 cell differentiation in the setting of acute injury, the role of this pathway may be context-and disease-dependent, as ectopic activation can be deleterious (22,32,42).…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

Wang

Michki

Banaschewski

et al. 2023

Preprint

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Hermansky-Pudlak syndrome (HPS) is a genetic disorder of intracellular endosomal trafficking defects associated with pulmonary fibrosis. Double mutant HPS1/2 mice exhibit spontaneous fibrosis and single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity. To identify mechanisms of AT2 cell dysfunction contributing to fibrosis in HPS, we examined lungs from aged HPS1/2 mice and observed regions of AT2 cell loss adjacent to areas of marked AT2 cell hyperplasia as compared to wild type (WT). Overall, there was accelerated loss of AT2 cells in HPS1/2, HPS1, and HPS2 mice with aging based on immunohistochemistry and lineage tracing studies. Lung organoids generated with HPS2 AT2 cells with WT fibroblasts were smaller in size and displayed significantly decreased colony forming efficiency compared to organoids with WT AT2 cells. Utilizing an H1N1 PR8 influenza model to examine AT2 cell regeneration after injury, there was a significant decrease in the percentage of proliferating AT2 cells in HPS1 and HPS2 mice compared to WT mice. RNA sequencing of AT2 cells isolated from unchallenged mice demonstrated upregulation of genes associated with proliferation and cellular senescence in HPS AT2 cells. Collectively, AT2 cells in HPS mice exhibit dysregulated proliferation with transcriptomic features suggesting subpopulations of senescent and hyperproliferative cells. Dysregulated maintenance of the alveolar epithelium with accelerated senescence and aberrant proliferation of AT2 cells appears to be a shared pathway underlying HPS and other sporadic and genetic forms of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

Wang

Michki

Banaschewski

et al. 2023

Preprint

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“…98 During the evolution of lung adenocarcinomas (LUADs), single-cell transcriptomics analyses reveal that P53 promotes AT2 cell differentiation through direct DNA binding, chromatin remodeling, and induction of genes characteristic of AT1 cells, suppressing LUAD. 99 4.1.2 | Signaling pathways Many signaling pathways during development are crucial for alveolar epithelial cell repair and regeneration. For example, active bone morphogenetic protein (BMP) signaling maintains AT2 cell quiescence during homeostasis, inactivation of BMP signaling promotes AT2 cell proliferation, and reactivation of BMP signaling promotes AT2 cell differentiation.…”

Section: Transcription Factormentioning

confidence: 99%

“…Transcription factor FGF promotes AT2 cell proliferation [92] EGF promotes AT2 cell proliferation [92] ETV5 promotes AT2 cell proliferation, whose deletion promotes enhanced differentiation of AT2 to AT1 [95] KLF5 represses AT2 cell proliferation and enhances AT2 differentiation into AT1 [96] Tfcp2l1 loss inhibits self-renewal and promoted AT2-AT1 differentiation [97] Elevated P21 induces cell cycle arrest and damps the differentiation into AT1 cells [98] P53 promotes AT2 cell differentiation [99] Signaling pathways Inactivation of BMP signaling promotes AT2 cell proliferation, reactivation of BMP signaling promotes AT2 cell differentiation [100] Downregulation of the WNT/β-catenin signaling pathway induces AT2 cell differentiation [101] α7nAChR promotes AT2 cell proliferation and subsequently differentiates toward AT1 cells via the WNT7B signaling pathway [102] YAP/TAZ promotes the proliferation and differentiation of AT2 cells [103] TGF-β signaling is inhibited in proliferating cells, highly upregulated in intermediate cells, and subsequently downregulated in differentiated cells [91] Notch signaling is activated during the proliferation, subsequently, DLK1 inhibits Notch signaling, thereby promoting the completion of differentiation of AT2 into AT1 [153] Mechanical tension YAP nuclear importing promotes AT2 cell proliferation [108] CDC42-deficient AT2 cannot differentiate into AT1, resulting in continued mechanical stretching and fibrosis [109] Metabolism AMPK-PFKFB2 axis enhances glycolysis to produce ATP, promoting the remodeling of the cytoskeleton to complete the differentiation of AT2 cells to AT1 cells [110] NAD + regeneration controls epithelial cell differentiation by preventing ISR activation [111] MICU1-dependent mitochondrial Ca 2+ uptake modulates the differentiation process [112] Mesenchymal cells niche PDGFRα + lipofibroblasts support the growth and differentiation of AT2 cells [117] Interstitial cells secrete IL-6 and FGF7 promoting AT2 cell proliferation and differentiation [118] Interstitial cells secrete BMP4 inhibiting AT2 cell proliferation and differentiation [118] Specialized stromal fibroblasts that block the WNT signaling pathway promote the differentiation of AT2 cells [101] Endothelial cells niche PCECs secrete MMP14 promoting alveolar regeneration [120] Activated platelets stimulate CXCR4 and CXCR7 on PCEC...…”

Section: At2 Facultative Stem Cellmentioning

confidence: 99%

“…Following multiple bleomycin‐induced pulmonary fibrosis, elevated cyclin‐dependent kinase inhibitor 1A (P21) in AT2 cells induces cell cycle arrest and damps the differentiation into AT1 cells by disturbing the E1A‐binding protein P300 (P300)–β‐catenin interaction 98 . During the evolution of lung adenocarcinomas (LUADs), single‐cell transcriptomics analyses reveal that P53 promotes AT2 cell differentiation through direct DNA binding, chromatin remodeling, and induction of genes characteristic of AT1 cells, suppressing LUAD 99 …”

Section: Repair and Regeneration Mechanisms Of Alveolar Epithelium Fo...mentioning

confidence: 99%

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Repair and regeneration of the alveolar epithelium in lung injury

Wang,

et al. 2024

The FASEB Journal

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Considerable progress has been made in understanding the function of alveolar epithelial cells in a quiescent state and regeneration mechanism after lung injury. Lung injury occurs commonly from severe viral and bacterial infections, inhalation lung injury, and indirect injury sepsis. A series of pathological mechanisms caused by excessive injury, such as apoptosis, autophagy, senescence, and ferroptosis, have been studied. Recovery from lung injury requires the integrity of the alveolar epithelial cell barrier and the realization of gas exchange function. Regeneration mechanisms include the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and proteins. While alveoli are damaged, alveolar type II (AT2) cells proliferate and differentiate into alveolar type I (AT1) cells to repair the damaged alveolar epithelial layer. Alveolar epithelial cells are surrounded by various cells, such as fibroblasts, endothelial cells, and various immune cells, which affect the proliferation and differentiation of AT2 cells through paracrine during alveolar regeneration. Besides, airway epithelial cells also contribute to the repair and regeneration process of alveolar epithelium. In this review, we mainly discuss the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and transcription factors.

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Bispecific, Exosome‐Mimetic Lipid Nanoparticles Facilitate Dual siRNAs for Synergistic Therapy against Pancreatic Cancer

Wang,

Zhang,

Wang

et al. 2024

Adv Funct Materials

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While RNA therapeutics hold great promise for combating pancreatic ductal adenocarcinoma (PDAC), the limited therapy outcome due to the insufficient delivery efficiency of vehicles and inadequate innate therapeutic potency for single siRNA hinders the broader application. Herein, report bispecific, exosome‐mimetic lipid nanoparticles (EM‐LNPs) carrying high loads of siKras and siTP53, which can efficiently overcome layers of barriers to accumulate cytoplasm in vitro and in vivo and achieve synergistic treatment for PDAC tumors. EM‐LNPs inherit features of synthetic LNPs and the protein characteristics of exosomes with outer CD47 proteins, membrane‐inserted integrin α6β4, and connexin 43. The siRNAs‐loaded EM‐LNPs can efficiently evade the host immune clearance in the circulation, considerably accumulate and penetrate dense tumors, and simultaneously target EGFR/VEGF of PDAC cells, following leakage into the cytoplasm. The intracellular siKras and siTP53 achieved synergistic therapeutic effects for PDAC cells with as high as 20 times enhancement in vitro and 3.5 times increase in vivo, significantly suppressed xenograft PDAC tumors, considerably reduced lung metastasis, and vastly extended mice survival at a low injection dose. These results explore an approach for delivering multiple gene cargoes to dense PDAC tumors for synergistic therapeutics.

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p53 governs an AT1 differentiation programme in lung cancer suppression

Cited by 17 publications

References 73 publications

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

Repair and regeneration of the alveolar epithelium in lung injury

Bispecific, Exosome‐Mimetic Lipid Nanoparticles Facilitate Dual siRNAs for Synergistic Therapy against Pancreatic Cancer

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