bims-p53act 2025-12-21 papers

Genes Dev. 2025 Dec 15.

Gizem Efe, Katherine Cunningham, Anil K Rustgi, Carol Prives, James J Manfredi, Francisco J Sánchez-Rivera.

The discovery of the p53 tumor suppressor protein raised fundamental questions about cell cycle regulation that have spanned several decades. TP53 mutations are found in most human cancers, most frequently as missense alterations in the DNA-binding domain (DBD). As a master regulator of both cell-intrinsic and cell-extrinsic functions, mutant p53 contributes to pro-oncogenic activities through gain-of-function (GOF) properties in addition to loss-of-function (LOF) and dominant-negative effects (DNEs). New technologies and improved fidelity of model systems are uncovering the functional consequences caused by p53 mutations at the molecular, cellular, and tissue levels. In a new era of precision medicine, with the context of recent success in targeting genetic mutations, ongoing and future understanding of fundamental mutant p53 biology is of paramount importance.

Keywords: dominant-negative effect; gain of function; loss of function; p53 mutation

DOI: https://doi.org/10.1101/gad.353408.125

J Proteome Res. 2025 Dec 16.

Multilayered Regulatory Dynamics of p53 Mutations and Platinum Resistance in Ovarian Cancer.

Liling Hu, Hanchen Zou, LvYing Peng, Fan Li, Danya Liu, Jiangli Lu, Yuying Li, Chris Zhiyi Zhang, Qiu-Hong Tian.

TP53 mutation-driven gene expression programs define oncogenic phenotypes. While extensive studies have concentrated on the transcriptome and proteome, post-transcriptional processes, particularly translational variation, remain underexplored. This study presents a comprehensive analysis of the transcriptomics, translatiomics, and proteomics dynamics in the ovarian cancer cell line SKOV3, with a focus on the effects of p53 missense mutations (R175H, R273H, and Y220C) on gene dosage fluctuations. Despite clear transcriptional differences between wild-type and mutant p53, we find that extensive translational and post-translational buffering processes attenuate these discrepancies, yielding comparatively stable protein abundances. Moreover, we delineate that the relative contributions of transcription output, translation engagement, and protein stability collectively shape the final protein abundance in the context of p53 mutations. Clinical proteomic analysis of platinum-resistant ovarian cancer tissues reveals tumor-specific factors and acquired resistance pathways linked to p53 mutations. Our findings elucidate the multilayered regulatory landscape of p53 mutations and identify potential risk factors for platinum resistance associated with these mutations.

Keywords: multiomics integration; ovary cancer; p53 mutation; platinum resistance; translatomics

DOI: https://doi.org/10.1021/acs.jproteome.5c00657

BMC Cancer. 2025 Dec 15. 25(1): 1868

Engineered hUCMSC-derived extracellular vesicles deliver circ-0000258 to restore p53-mediated tumor suppression in papillary thyroid carcinoma.

Chan Zhang, Lei Li, Yanxiu Liu, Bo Yu, Jing Liu, Shujing Li.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is a significant type of endocrine cancer, characterized by diverse genetic alterations and a complex molecular environment. Extracellular vesicles (EVs), especially those derived from mesenchymal stem cells (MSCs), have emerged as promising targeted drug carriers for cancer cells. Additionally, reprogramming MSC-derived EVs represents a novel strategy for cancer gene therapy, offering potential solutions to clinical challenges and new treatment directions. Increasing evidence suggests that MSC-derived EVs play a crucial role in tumor progression by delivering circular RNAs (circRNAs), which function as microRNA (miRNA) sponges. However, the underlying molecular mechanisms and their clinical applications remain to be fully explored and validated.
METHODS AND RESULTS: Through in-depth mining using high-throughput bioinformatics analyses, we conducted a comprehensive differential gene analysis between PTC tissues and normal thyroid tissues, successfully identifying circ-0000258 as a key regulatory molecule. Following multi-dimensional validation in PTC cell lines and clinical specimens, the consistent low expression of circ-0000258 was confirmed, strongly suggesting its latent potential as a tumor suppressor. Functional mechanistic investigations have revealed that overexpression of circ-0000258 potently curbs the malignant biological behaviors of PTC cells, notably inhibiting cell proliferation and invasion. More significantly, circ-0000258 acts as a molecular sponge, specifically sequestering miR-146b. This action relieves the post-transcriptional repression of p53 by miR-146b, thereby activating the p53-mediated apoptotic signaling cascade. By intervening at the genetic regulatory level, circ-0000258 effectively reprograms the fate of thyroid tumor cells. Furthermore, in the context of translational medicine research, we innovatively constructed an engineered delivery platform based on extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUCMSC-EVs). By exogenously loading circ-0000258 into these vesicles, we successfully endowed these natural nanocarriers with targeted anti-cancer properties. Both in vitro and in vivo functional assays demonstrated that the engineered hUCMSC-EVs loaded with circ-0000258 could effectively act on PTC cells, significantly reducing the volume of xenograft tumors and inducing tumor cell apoptosis. Notably, when combined with cisplatin, these engineered extracellular vesicles exhibited a synergistic anti-cancer effect, suggesting their potential to overcome chemoresistance in thyroid tumors.
CONCLUSION: This study has established the circ-0000258/miR-146b/p53 regulatory axis as a crucial mechanism underlying tumor suppression in PTC. It has also demonstrated the translational potential of hUCMSC-EVs as a safe and efficient delivery vehicle. By integrating the functional role of circ-0000258 with the targeted delivery advantages of engineered EVs, this research not only provides a novel strategy for the targeted treatment of thyroid cancer but also offers a theoretical basis and technical paradigm for the development of novel anti-tumor biological agents. It is anticipated to advance the field of precision oncology to a new level.

Keywords: Circ-0000258; HUCMSC-Extracellular vesicles; Molecular sponge; P53 pathway; Papillary thyroid carcinoma

DOI: https://doi.org/10.1186/s12885-025-15230-5

Int J Gynecol Cancer. 2025 Nov 21. pii: S1048-891X(25)01951-6. [Epub ahead of print]36(2): 102829

Association between molecular classification and overall survival in patients with metastatic endometrial carcinoma: ancillary results of the UTOLA phase II GINECO trial.

OBJECTIVE: We aimed to describe the association between molecular sub-groups and outcomes in patients with advanced/metastatic endometrial carcinoma amenable to maintenance/active surveillance after carboplatin-based chemotherapy.
METHODS: Patients treated in the GINECO trial UTOLA (NCT03745950, randomly allocating patients 2:1 to olaparib/placebo after tumor control under carboplatin-based chemotherapy), with prospective centralized targeted next-generation sequencing, and mismatch repair and p53 immunostainings were included. Next-generation sequencing (667.5 kb) included POLE (exo-nuclease domain), TP53, PIK3CA, PIK3R1, PTEN, KRAS, and CTNNB1. Tumors were categorized following the 2022 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines as POLE-mutated, mismatch repair-deficient, p53-abnormal (immunostaining or TP53 mutation), and with no specific molecular profile. Exploratory analyses categorized non-p53-abnormal tumors based on literature (mismatch repair-deficient: mutational burden; no specificity: PIK3R1/PTEN wild-type tumors, CTNNB1/KRAS-mutated tumors, others).
RESULTS: Among 145 patients in the intention to treat population (median follow-up 31 months), 1, 21 (15%), 76 (53%), and 45 (32%) had POLE, mismatch repair-deficient, p53-abnormal, and non-specific tumors (2 missing mismatch repair), respectively. Molecular characterization was associated with progression-free (log-rank, p = .017) and overall survival (p < .001). Patients with p53abn tumors had a hazard ratio for death of 2.43, 95% confidence interval 1.50 to 3.93 (adjusted on age, stage IV, measurable lesions after chemotherapy). Exploratory analyses showed high mutational burden mismatch repair-deficient tumors with prognostic similar to p53abn tumors, whereas tumors with lower mutational burden had better progression-free survival. PIK3R1/PTEN wild-type and CTNNB1/KRAS-mutated non-specific tumors had better outcomes than p53abn tumors. Other non-specific tumors have survival similar to p53abn tumors.
CONCLUSIONS: Integration of molecular sub-group as a stratification parameter might be considered for randomized trials in advanced/metastatic endometrial carcinoma after carboplatin-based chemotherapy. Deeper characterization of mismatch repair-proficient tumors might enhance prognostication.

Keywords: Endometrial Carcinoma; Molecular Characterization; Molecular Group; Personalized Oncology

DOI: https://doi.org/10.1016/j.ijgc.2025.102829

Leukemia. 2025 Dec 17.

The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis.

Jonas Fullin, Ebru Topçu, Karolina A Zielińska, Roman R Schimmer, Nancy Klemm, Christian Koch, Francisco Caiado, Melissa Lock, Cyril Doerdelmann, Marco M Bühler, Joelle Tchinda, Kari J Kurppa, Lubor Borsig, Philip H Jones, Massimo Lopes, Markus G Manz, Steffen Boettcher.

Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) - a condition termed clonal hematopoiesis (CH) - are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.

DOI: https://doi.org/10.1038/s41375-025-02839-5