Frontiers in Cell and Developmental Biology最新文献

{"title":"Placental trophoblast aging in advanced maternal age is related to increased oxidative damage and decreased YAP.","authors":"Song Guo, Qihao Pan, Baokang Chen, Yijuan Huang, Si Li, Chenyu Gou, Yu Gao","doi":"10.3389/fcell.2025.1479960","DOIUrl":"10.3389/fcell.2025.1479960","url":null,"abstract":"<p><strong>Introduction: </strong>The advanced maternal age (AMA) pregnancies escalate rapidly, which are frequently linked to higher risks of adverse outcomes. Advanced maternal age (AMA) placenta exhibited premature aging, presumably resulting in trophoblast dysfunction, inadequate placentation. However, the precise reasons and mechanisms of trophoblast aging in AMA placenta remain unclear, posing a significant limitation to provide effective guidance for prenatal healthcare in clinical settings. Notably, the organism shows heightened vulnerability to oxidative damage as it ages. YAP (Yes-associated protein) was reported to play a critical role in regulation of aging and resisting oxidative damage, yet these roles had not been elucidated in the placenta. Therefore, this study explored the relationship between trophoblast cell aging and oxidative injury and YAP in AMA pregnancy, which not only provided an insight into the mechanisms of trophoblast cell aging, but also provide valuable directions for healthcare during AMA pregnancy.</p><p><strong>Methods: </strong>In this study, human term placentas were collected from AMA and normal pregnancies for the analysis of aging, oxidative damage and YAP level. HTR8/SVneo cells were manipulated with (hydrogen peroxide) H₂O₂ to explore the effects of oxidative damage on trophoblast cell senescence and YAP levels. YAP expression in HTR8/SVneo cells was manipulated to investigate its role in trophoblastic senescence and oxidative damage.</p><p><strong>Results: </strong>Compared with the control group, the AMA placenta exhibits increased aging biomarkers, which is coupled with an elevation in oxidative damage within placental trophoblast cells and a notable decline in YAP levels. Cellular experiments demonstrated that oxidative damage from H₂O₂ triggered trophoblast cell senescence and resulted in a reduction of YAP levels. Furthermore, employing molecular modification to silence YAP expression in these cells led to an induction of aging. Conversely, overexpressing YAP ameliorated both trophoblast cell aging and the associated DNA oxidative damage that arised from H₂O₂.</p><p><strong>Conclusion: </strong>The decline of YAP in AMA pregnancy should be responsible for the increased oxidative injury and premature placenta aging, indicating that YAP plays a significant role in combating oxidative damage and delaying aging, thereby providing a new guidance for prenatal care in AMA pregnancies. Maintaining YAP levels or implementing anti-oxidative stress interventions could potentially mitigate the incidence of complications involved AMA pregnancy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1479960"},"PeriodicalIF":4.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of agarose/gelatin gel addition on the pro-angiogenic potential of polyhydroxybutyrate/chitosan scaffolds.","authors":"Mária Giretová, Ľubomír Medvecký, Zuzana Demčišáková, Lenka Luptáková, Eva Petrovová, Radoslava Štulajterová","doi":"10.3389/fcell.2024.1504268","DOIUrl":"10.3389/fcell.2024.1504268","url":null,"abstract":"<p><p>The aim of this paper was to evaluate the effect of gel addition to biopolymeric scaffolds on the pro-angiogenic and basic material characteristics of the final composite for use in regenerative medicine. The studied scaffold consisted of natural biopolymers: polyhydroxybutyrate, chitosan, agarose, and gelatin. The final scaffold was characterized by high macroporosity (90%) and wide pore size distribution. As is known, the pore size is a critical factor for cell ingrowth in grafts after implantation in the body and for angiogenic development and creation of new vessels. After 9 days of cultivation in the culture medium, the scaffold retained its physicochemical properties without any tendency of disintegration. The addition of polymeric gels to the scaffold improved the mechanical stability of the composite. <i>In vitro</i> cytotoxicity testing showed good adherence of the seeded L929 fibroblasts on the scaffold and strong ingrowth of cells into the macropores. No sign of cytotoxicity was identified by both the MTS assay and live/dead cell staining. The quail chorioallantoic membrane (CAM) assay-as an alternative to <i>in vivo</i> assays-revealed suitable pro-angiogenic properties of the scaffold for the formation and ingrowth of new blood vessels. Moreover, the upregulation of gene expression responsible for the activation of angiogenic cascade clearly demonstrated a positive effect of the prepared composites on angiogenesis as an essential part of new tissue formation and the regeneration process itself.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1504268"},"PeriodicalIF":4.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia signature derived from tumor-associated endothelial cells predict prognosis in gastric cancer.","authors":"Ruiheng Wang, Guijun Liu, Ke Wang, Zhanglei Pan, Zhihua Pei, Xijiao Hu","doi":"10.3389/fcell.2025.1515681","DOIUrl":"10.3389/fcell.2025.1515681","url":null,"abstract":"<p><strong>Background: </strong>A hypoxic metabolism environment in the tumors is often associated with poor prognostic events such as tumor progression and treatment resistance. In gastric cancer, the mechanism of how hypoxia metabolism affects the tumor microenvironment and immunotherapy efficacy remains to be elucidated.</p><p><strong>Methods: </strong>We used the bulk-mapping method to analyze the signatures correlated with the response of immunotherapy in the single-cell dataset. Cellular, pathway, and gene were systematically analyzed in both single-cell and bulk validation datasets.</p><p><strong>Results: </strong>The most significant cell proportion difference between the response and non-response groups was in endothelial cells, which represent the malignant cells. VWF was specifically overexpressed in endothelial cells and was the hub gene of differential genes. EPAS1 was a VWF trans-regulated gene and highly positively correlated with VWF in expression. Knockdown experiments demonstrated that siVWF reduced the expression of VWF, EPAS1, and HIF1A, as well as the synthesis of lactate and adenosine which are indicators of hypoxic metabolism. These results suggest that the overexpression of core malign endothelial genes such as VWF drives hypoxic metabolism in tumors and creates an immunosuppressive environment that reduces the efficacy of immunotherapy. The adverse prognosis of the hypoxia signature was validated in the bulk cohort and significance was further enhanced after selecting core genes and combined survival weight scoring.</p><p><strong>Conclusion: </strong>In summary, high expression of the malignant endothelial cell driver genes VWF and EPAS1 enhances hypoxic metabolism, and malignant cell-immune cell interactions suppress the immune response. Therefore, the two core genes of hypoxic metabolism might represent potential therapeutic and predicting biomarkers for immunotherapy of gastric cancer in the future.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1515681"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of renal cell carcinoma metastasis and potential targets for therapy.","authors":"Xinwei Li, Wei Xiong, Zhiyong Xiong, Xiaoping Zhang","doi":"10.3389/fcell.2025.1521151","DOIUrl":"10.3389/fcell.2025.1521151","url":null,"abstract":"<p><p>Renal cell carcinoma is a common type of cancer, with approximately 30% of patients potentially developing metastatic disease. Some patients with metastatic renal cell carcinoma are found in advanced stages, so the 5-year survival rate for metastatic renal cell carcinoma is only 14%. Currently, there are several drugs available for patients with metastatic renal cell carcinoma, and their overall survival can be extended to nearly 5 years. However, the sensitivity and efficacy of the treatment are still unsatisfactory. New targets and drugs to improve patient prognosis are urgently needed, but these are closely linked to the molecular mechanisms of renal cell carcinoma metastasis. In this review, we present the definition and common molecular mechanisms of metastatic renal cell carcinoma and provide new insights on their potential link to targeted therapies, which may enlighten scientists to develop future targeted therapeutic agents to improve the prognosis of patients with metastatic renal cell carcinoma.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1521151"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network.","authors":"Yi Wang, Moran Xu, Xiaoli Zuo, Sheng Wang, Yong Yu, Zhaobing Gao, Jingbo Qie, Ye Jiang, Fang Huang, Bingqing Xia","doi":"10.3389/fcell.2024.1509877","DOIUrl":"10.3389/fcell.2024.1509877","url":null,"abstract":"<p><strong>Introduction: </strong>Mixed Lineage Kinase Domain-Like Protein (MLKL), as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential as a therapeutic target to mitigate posthemorrhagic stroke damage. However, the mechanisms by which MLKL functions in the process of intracerebral hemorrhage (ICH)-induced damage remain unclear.</p><p><strong>Methods: </strong>Here, we explored the correlation between MLKL and pathological damage in ICH patients through histopathological staining and RT-qPCR. Furthermore, we established an intracerebral hemorrhage model by collagenase IV injection in WT and <i>Mlkl^-/-</i> mice. Subsequently, we investigated the impact of MLKL knockout on ICH pathological damage through behavioral tests, Western blotting, and RT-qPCR. Finally, we performed a proteomic analysis via LC-MS/MS to explore the potential interacting proteins of MLKL in the progression of ICH.</p><p><strong>Results: </strong>We found that MLKL is highly expressed in the brain tissue of ICH patients and is positively correlated with the extent of injury. However, we found that Mlkl knockout alone was insufficient to fully reverse neuroinflammation and pathological damage. Although Mlkl knockout has a limited effect on alleviating ICH damage, proteomics results indicate that MLKL can mitigate changes in proteins associated with inflammation, metabolism, and coagulation pathways, suggesting that MLKL may exert its effects through these pathways.</p><p><strong>Discussion: </strong>In summary, our results suggest that although MLKL is associated with the progression of ICH, single knockout of Mlkl is insufficient to fully reverse the pathological damage of ICH. Proteomic analysis indicates that co-targeting MLKL and its associated protein network may yield better therapeutic outcomes for hemorrhagic stroke.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1509877"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myogenesis gone awry: the role of developmental pathways in rhabdomyosarcoma.","authors":"Annika L Gustafson, Adam D Durbin, Kristin B Artinger, Heide L Ford","doi":"10.3389/fcell.2024.1521523","DOIUrl":"10.3389/fcell.2024.1521523","url":null,"abstract":"<p><p>Rhabdomyosarcoma is a soft-tissue sarcoma that occurs most frequently in pediatric patients and has poor survival rates in patients with recurrent or metastatic disease. There are two major sub-types of RMS: fusion-positive (FP-RMS) and fusion-negative (FN-RMS); with FP-RMS typically containing chromosomal translocations between the <i>PAX3/7-FOXO1</i> loci. Regardless of subtype, RMS resembles embryonic skeletal muscle as it expresses the myogenic regulatory factors (MRFs), MYOD1 and MYOG. During normal myogenesis, these developmental transcription factors (TFs) orchestrate the formation of terminally differentiated, striated, and multinucleated skeletal muscle. However, in RMS these TFs become dysregulated such that they enable the sustained properties of malignancy. In FP-RMS, the <i>PAX3/7-FOXO1</i> chromosomal translocation results in restructured chromatin, altering the binding of many MRFs and driving an oncogenic state. In FN-RMS, re-expression of MRFs, as well as other myogenic TFs, blocks terminal differentiation and holds cells in a proliferative, stem-cell-like state. In this review, we delve into the myogenic transcriptional networks that are dysregulated in and contribute to RMS progression. Advances in understanding the mechanisms through which myogenesis becomes stalled in RMS will lead to new tumor-specific therapies that target these aberrantly expressed developmental transcriptional pathways.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1521523"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trafficking in cancer: from gene deregulation to altered organelles and emerging biophysical properties.","authors":"Julie Patat, Kristine Schauer, Hugo Lachuer","doi":"10.3389/fcell.2024.1491304","DOIUrl":"10.3389/fcell.2024.1491304","url":null,"abstract":"<p><p>Intracellular trafficking supports all cell functions maintaining the exchange of material between membrane-bound organelles and the plasma membrane during endocytosis, cargo sorting, and exocytosis/secretion. Several proteins of the intracellular trafficking machinery are deregulated in diseases, particularly cancer. This complex and deadly disease stays a heavy burden for society, despite years of intense research activity. Here, we give an overview about trafficking proteins and highlight that in addition to their molecular functions, they contribute to the emergence of intracellular organelle landscapes. We review recent evidence of organelle landscape alterations in cancer. We argue that focusing on organelles, which represent the higher-order, cumulative behavior of trafficking regulators, could help to better understand, describe and fight cancer. In particular, we propose adopting a physical framework to describe the organelle landscape, with the goal of identifying the key parameters that are crucial for a stable and non-random organelle organization characteristic of healthy cells. By understanding these parameters, we may gain insights into the mechanisms that lead to a pathological organelle spatial organization, which could help explain the plasticity of cancer cells.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1491304"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of disulfidptosis-related genes and the immune microenvironment in heart failure.","authors":"Linna Zhao, Juanjuan Zhang, Qiuhang Song, Cheng Dai, Yiping Qin, Aiying Li","doi":"10.3389/fcell.2024.1516898","DOIUrl":"10.3389/fcell.2024.1516898","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF) is a prevalent cardiovascular disease that currently lacks effective treatment options due to its intricate pathogenesis. A recent study has linked disulfidoptosis, a novel form of cell demise, with the development of a range of diseases. Nonetheless, the effect of disulfidoptosis on the immune microenvironment of HF is not well comprehended. In this paper, bioinformatics analysis was performed to investigate how disulfidptosis-related genes (DRGs) affect the immune microenvironment of HF.</p><p><strong>Methods: </strong>The expression of four DRGs was initially examined using bulk RNA-Seq and single-cell RNA sequencing data. A predictive model was subsequently developed. Consensus clustering was used to distinguish between the two clusters of DRGs. The effect of these DRGs on the characteristics of the immune microenvironment was further explored, such as infiltrating immune cells, immune response gene sets, and HLAs genes.</p><p><strong>Results: </strong>All four DRGs were dysregulated in HF samples. The predictive model based on these four DRGs effectively differentiated between HF patients and healthy individuals, which was validated in the experiment. These four DRGs were strongly associated with the abundance of infiltrating monocytes. Moreover, our analysis identified two distinct clusters of DRGs and these clusters exhibited differences in terms of immune cell abundance, immune response, and HLA gene expression. The biological functions associated with these differences were also revealed.</p><p><strong>Conclusion: </strong>Our discovery underscores the pivotal role of DRGs in shaping the diversity and intricacy of the immune microenvironment in HF.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1516898"},"PeriodicalIF":4.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARGC1A regulates transcriptional control of mitochondrial biogenesis in early bovine embryos.","authors":"Muhammad Idrees, Zaheer Haider, Chalani Dilshani Perera, Safeer Ullah, Seo-Hyeon Lee, Seung Eun Lee, Sung-Sik Kang, Sung Woo Kim, Il-Keun Kong","doi":"10.3389/fcell.2024.1531378","DOIUrl":"10.3389/fcell.2024.1531378","url":null,"abstract":"<p><p>Extensive mitochondrial replication during oogenesis and its role in oocyte maturation and fertilization indicate that the amount of mitochondrial DNA (mtDNA) may play a significant role in early embryonic development. Early embryos express peroxisome proliferator-activated receptor gamma co-activator alpha (PPARGC1A/PGC-1a), a protein essential for mitochondrial biogenesis. This study investigated the role of PGC-1α from a single-cell zygotic stage to day-8 bovine blastocyst and the effect of PGC-1a knockdown (KD) on embryo mitochondria and development. PGC-1α KD via siRNA injection into single-cell zygotes does not substantially affect embryonic cleavage up to the morula stage but considerably reduces blastocyst development (18.42%) and hatching than the control (32.81%). PGC-1α regulates transcription of the gene encoding mitochondrial transcription factor A (TFAM), and immunofluorescence analysis indicated significantly lower TFAM expression in the 16-cell KD embryos and day-8 KD blastocysts. Reduction in NRF1 protein's nuclear localization in bovine blastomeres was also observed in PGC-1α-KD embryos. Furthermore, to understand the effect of PGC-1α-KD on the mitochondrial genome, we found a low mtDNA copy number in PGC-1α-KD day-8 bovine blastocysts. Several genes related to mitochondrial functioning, like ND1, ND3, ND5, ATPase8, COI, COII, and CYTB, were significantly downregulated in PGC-1α-KD embryos. Moreover, high mitochondrial depolarization (ΔΨm) and abnormal lipid depositions were observed in the PGC-1α KD blastocysts. SIRT1 is the upstream regulator of PGC-1α, but SIRT1 activation via Hesperetin does not affect PGC-1α-KD embryonic development considerably. In conclusion, PGC-1α plays a critical role in early embryo mitochondrial functioning, and any perturbation in its expression significantly disrupts early embryonic development.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1531378"},"PeriodicalIF":4.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GRHL2-HER3 and E-cadherin mediate EGFR-bypass drug resistance in lung cancer cells.","authors":"Fumiya Ito, Wakiko Iwata, Yoshihiro Adachi, Hiromi Sesaki, Miho Iijima","doi":"10.3389/fcell.2024.1511190","DOIUrl":"10.3389/fcell.2024.1511190","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) is a major oncogenic protein, and thus EGFR-targeting therapies are widely used in patients with various types of cancer, including lung cancer. However, resistance to EGFR inhibitors, such as erlotinib, presents a significant challenge in treating lung cancer. In this study, we established an EGFR-independent, erlotinib-resistant (ER) phenotype in lung cancer A549 cells by exposing them to erlotinib for an extended period. The resulting ER cells exhibited a dramatic increase in erlotinib resistance, a decreased EGFR protein level, and enhanced tumor growth, suggesting a robust mechanism bypassing EGFR inhibition. RNA sequencing identified the transcription factor GRHL2 as a critical player in this resistance. GRHL2 was upregulated in ER cells, and its knockdown and knockout significantly reduced erlotinib resistance. Further analysis revealed that GRHL2 upregulates the receptor tyrosine kinase HER3, and that HER3 knockdown similarly decreases the IC₅₀ for erlotinib. Additionally, ER cells showed increased cell-cell adhesion, linked to upregulated E-cadherin. E-cadherin was found to be vital for erlotinib resistance, largely independent of GRHL2, highlighting multiple parallel pathways sustaining resistance. These findings provide a novel mechanism of drug resistance and suggest that combination therapies targeting both GRHL2-HER3 and E-cadherin-mediated pathways may be necessary to overcome erlotinib resistance in lung cancer.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1511190"},"PeriodicalIF":4.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}