Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.

A kinome drug screen identifies multi-TKI synergies and ERBB2 signaling as a therapeutic vulnerability in MYC/TYR subgroup atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is a rare, devastating, and largely incurable pediatric brain tumor. Although recent studies have uncovered 3 molecular subgroups of ATRTs with distinct disease patterns, and signaling features, the therapeutic profiles of ATRT subgroups remain incompletely elucidated. METHODS: We examined the effect of 465 kinase inhibitors on a panel of ATRT subgroup-specific cell lines. We then applied multiomics analyses to investigate the underlying molecular mechanism of kinase inhibitor efficacy in ATRT subgroups. RESULTS: We observed that ATRT cell lines are broadly sensitive to inhibitors of the PI3K and MAPK signaling pathways, as well as CDKs, AURKA/B kinases, and polo-like kinase 1. We identified 2 classes of multikinase inhibitors predominantly targeting receptor tyrosine kinases including PDGFR and EGFR/ERBB2 in MYC/TYR ATRT cells. The PDGFRB inhibitor, Dasatinib, synergistically affected MYC/TYR ATRT cell growth when combined with broad-acting PI3K and MAPK pathway inhibitors, including Rapamycin and Trametinib. We observed that MYC/TYR ATRT cells were also distinctly sensitive to various inhibitors of ERBB2 signaling. Transcriptional, H3K27Ac ChIPSeq, ATACSeq, and HiChIP analyses of primary MYC/TYR ATRTs revealed ERBB2 expression, which correlated with differential methylation and activation of a distinct enhancer element by DNA looping. Significantly, we show the brain penetrant EGFR/ERBB2 inhibitor, Afatinib, specifically inhibited in vitro and in vivo growth of MYC/TYR ATRT cells. CONCLUSIONS: Taken together, our studies suggest combined treatments with PDGFR and ERBB2-directed TKIs with inhibitors of the PI3K and MAPK pathways as an important new therapeutic strategy for the MYC/TYR subgroup of ATRTs.

Assessment of Molecular Markers in Pediatric Ovarian Tumors: Romanian Single-Center Experience.

Pediatric ovarian tumors exhibit unique diagnostic and therapeutic challenges. This study evaluates the expression of SALL4 and OCT3/4 biomarkers in pediatric ovarian tumors and their associations with tumor subtype, stage, and clinical outcome. A retrospective analysis was conducted on 64 patients under 18 years old, examining demographic data, tumor characteristics, immunohistochemical staining, and clinical outcomes. Our results show that SALL4 was significantly expressed in adenocarcinoma, dysgerminoma (DSG), mixed germ cell tumors (GCTs), and immature teratoma, while OCT3/4 was highly expressed in DSG and mixed GCTs. Both markers are associated with a higher tumor grade and stage, indicating a more aggressive disease. The SALL4 positivity expression was correlated with high alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) levels, while OCT3/4 positivity significantly predicted the risk of subsequent metastasis. The mean progression-free survival (PFS) was notably shorter in patients with positive markers. These findings underscore the diagnostic and prognostic value of SALL4 and OCT3/4 in pediatric ovarian tumors, aligning with previous research and supporting their use in clinical practice for better disease management and patient outcomes.

Generation of a human induced pluripotent stem cell line (SHUPLi002-A) from PBMCs of a healthy female donor.

Human induced pluripotent stem cells (iPSCs) have good multi-lineage differentiation potential, which is an ideal model for studying the pathogenesis of diseases and drug screening.Here, we generated an iPSC line, SHUPLi002-A, from peripheral blood mononuclear cells (PBMCs) of a healthy 28-year-old female individual using episomal vectors. SHUPLi002-A is characterized by expression of classical pluripotent stem cell markers as well as teratoma formation assays to evaluate their differentiation capacity in vivo.

Generation of induced pluripotent stem cells (ZZUCSBi001-A) from skin fibroblasts of a healthy donor.

Fibroblasts were extracted from the scalp of a healthy 55-year-old male and subsequently transformed into pluripotent stem cells by introducing episomal plasmids harboring essential reprogramming factors. These induced pluripotent stem cells exhibited a normal karyotype and demonstrated the capacity to differentiate into all three germ layers, as confirmed through teratoma assays. This specific cell line serves as a valuable reference for comparative investigations alongside other induced pluripotent stem cell lines generated from somatic cells of patients afflicted by genetic neurodegenerative disorders.

Decoding the universal human chromatin landscape through teratoma-based profiling.

Teratoma formation is key for evaluating differentiation of human pluripotent stem cells into embryonic germ layers and serves as a model for understanding stem cell differentiation and developmental processes. Its potential for insights into epigenome and transcriptome profiling is significant. This study integrates the analysis of the epigenome and transcriptome of hESC-generated teratomas, comparing transcriptomes between hESCs and teratomas. It employs cell type-specific expression patterns from single-cell data to deconvolve RNA-Seq data and identify cell types within teratomas. Our results provide a catalog of activating and repressive histone modifications, while also elucidating distinctive features of chromatin states. Construction of an epigenetic signature matrix enabled the quantification of diverse cell populations in teratomas and enhanced the ability to unravel the epigenetic landscape in heterogeneous tissue contexts. This study also includes a single cell multiome atlas of expression (scRNA-Seq) and chromatin accessibility (scATAC-Seq) of human teratomas, further revealing the complexity of these tissues. A histology-based digital staining tool further complemented the annotation of cell types in teratomas, enhancing our understanding of their cellular composition. This research is a valuable resource for examining teratoma epigenomic and transcriptomic landscapes and serves as a model for epigenetic data comparison.

Characterizing the mutational burden, DNA methylation landscape, and proteome of germ cell tumor-related somatic-type malignancies to identify the tissue-of-origin, mechanisms of therapy resistance, and druggable targets.

BACKGROUND: Germ cell tumors (GCT) might undergo transformation into a somatic-type malignancy (STM), resulting in a cell fate switch to tumors usually found in somatic tissues, such as rhabdomyosarcomas or adenocarcinomas. STM is associated with a poor prognosis, but the molecular and epigenetic mechanisms triggering STM are still enigmatic, the tissue-of-origin is under debate and biomarkers are lacking. METHODS: To address these questions, we characterized a unique cohort of STM tissues on mutational, epigenetic and protein level using modern and high-throughput methods like TSO assays, 850k DNA methylation arrays and mass spectrometry. RESULTS AND CONCLUSIONS: For the first time, we show that based on DNA methylation and proteome data carcinoma-related STM more closely resemble yolk-sac tumors, while sarcoma-related STM resemble teratoma. STM harbor mutations in FGF signaling factors (FGF6/23, FGFR1/4) highlighting the corresponding pathway as a therapeutic target. Furthermore, STM utilize signaling pathways, like AKT, FGF, MAPK, and WNT to mediate molecular functions coping with oxidative stress, toxin transport, DNA helicase activity, apoptosis and the cell cycle. Collectively, these data might explain the high therapy resistance of STM. Finally, we identified putative novel biomarkers secreted by STM, like EFEMP1, MIF, and DNA methylation at specific CpG dinucleotides.

APE1 promotes embryonic stem cell proliferation and teratoma formation by regulating GDNF/GFRα1 axis.

The teratomas formation has severely hindered the application of embryonic stem cells (ESCs) in clinical trials. Apurinic/apyrimidinic endonuclease 1 (APE1) is strongly involved in the development of tumors and differentiation process of stem cells. However, the role of APE1 in teratomas remains unknown. The expression of APE1 was examined in mouse ESCs (mESCs) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of APE1 in the proliferation, pluripotency and differentiation of E14 cells were determined by cell counting, flow cytometry and western blot assays. Besides, the role of APE1 in teratomas was also probed in xenografted mice. The expression of APE1 was upregulated in mESCs with differentiation. Knockdown of APE1 reduced the cell numbers, induced the arrest of the G2/M phase, and decreased the expression of cell cycle-related proteins in E14 cells. Besides, loss- and gain-of-function assays revealed that APE1 enhanced the levels of proteins involved in pluripotency, reduced the protein expression of ectoderm markers, and increased the protein levels of endoderm markers in E14 cells. Mechanically, inhibition of APE1 downregulated the expression of GDNF and GFRα1 in E14 cells. GDNF reversed the role of APE1 in the proliferation, pluripotency and embryogenesis of E14 cells. Moreover, suppression of APE1 reduced the teratoma volume and the relative protein expression of endoderm markers, but increased the relative protein expression of ectoderm markers in xenografted mice. Collectively, knockdown of APE1 attenuated proliferation, pluripotency and embryogenesis of mESCs via GDNF/GFRα1 axis.

The Mc4r gene is responsible for the development of experimentally induced testicular teratomas.

Teratomas in mice, composed of different tissue types, are derived from primordial germ cells in the fetal gonads. Previously, we identified a locus responsible for experimental testicular teratoma (ETT) formation on chromosome 18, referred to as ett1. The strongest candidate sequence in the ett1 locus was found to be a missense mutation in the melanocortin 4 receptor (Mc4r), Mc4rG25S. We established a strain with a point mutation in the Mc4r gene in the ETT-nonsusceptible LT strain, called LT- Mc4rG25S, by genome editing. Surprisingly, highly developed ovarian teratomas (OTs), rather than testicular teratomas, appeared in the LT-Mc4rG25S strain. The results demonstrated that Mc4r is also one of the genes responsible for OT formation and suggested that missense mutations in Mc4r promote teratoma formation in both sexes. In this study, we performed ETT experiments in different host-graft combinations of the LT-Mc4rG25S and LT strains. Furthermore, the expression of MC4R in germ cells in the testis was demonstrated. Expression of Mc4r in testis was also confirmed by RT-PCR. The results demonstrated that MC4R is expressed in germ cells in the testis and that a point mutation in the Mc4r gene is responsible for ETT formation.

Efficient generation of induced pluripotent stem cell lines from peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) have been widely considered as a more convenient and almost unlimited reprogramming resource, while the reprogramming procedure and efficiency still need to be improved. We reprogrammed the PBMCs by using non-integrative non-viral vectors liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The iPSC lines exhibited a normal karyotype with their corresponding PBMCs and exhibited significant cellular pluripotency. Teratoma formation assay revealed that the iPSCs we generated could differentiate into three embryonic germ layers. Our study provides a more effective procedure for peripheral blood monocyte reprogramming to iPSC, and promotes its future application.

Pluripotent stem cells: Basic biology or else differentiations aimed at translational research and the role of flow cytometry.

Pluripotent stem cell research has revolutionized the modern era for the past 14 years with the advent of induced pluripotent stem cells. Before this time, scientists had access to human and mouse embryonic stem cells primarily for basic research and an attempt towards lineage-specific differentiations for cell therapy applications. Regarding pluripotent stem cells, expression of bonafide marker proteins such as Oct4, Nanog, Sox2, Klf4, c-Myc, and Lin28 have been considered giving a perfect readout for pluripotent stem cells and assessed using an analytical flow cytometer. In addition to the intracellular markers, surface markers such as stage-specific embryonic antigen-1 for mouse cells and SSEA-4 for human cells are needed to sort pure populations of stem cells for further downstream applications for cell therapy. The surface marker SSEA-4 is the most appropriate for obtaining pure populations of human pluripotent stem cells. When differentiated in a controlled manner using growth factors or small molecules, it is mandatory to assess the downregulation of pluripotency markers (Oct4, Nanog, Sox2, and Klf4) with subsequent up-regulation of stage-specific differentiation markers. Such assessments are done using flow cytometry. Pluripotent stem cells have a high teratoma-forming potential in vivo. Small amounts of undifferentiated PSCs might lead to dangerous teratomas upon transplantation if leftover in the pool of differentiated cells. Hence, flow cytometry is essential for sorting out PSC populations with teratoma-forming potential. The pure populations of differentiated progenitors need to be flow-sorted before differentiating them further for cell therapy applications. For example, Glycoprotein 2 is a specific cell-surface marker for pancreatic progenitors that enables one to sort the pancreatic progenitors differentiated from human PSCs. Taken together, analytical flow cytometry, and cell sorting provide indispensable tools in PSC research and cell therapy.

DUSP5 and PHLDA1 mutations in mature cystic teratomas of the ovary identified on whole-exome sequencing may explain teratoma characteristics.

BACKGROUND: Mature cystic teratomas of the ovary are the most common type of germ cell tumor, comprising 33% of ovarian tumors. Studying these tumors may result in a better understanding of their stepwise developmental processes and molecular bases and provide useful information for the development of tissue-engineering technologies. METHODS: In the present study, 9 mature cystic teratomas of the ovary were analyzed by whole-exome sequencing and the results were compared with the Catalogue of Somatic Mutations in Cancer and dbSNP databases. RESULTS: Mutations were validated in 15 genes with alterations in all 9 (100%) samples and changes in protein coding. The top 10 mutated genes were FLG, MUC17, MUC5B, RP1L1, NBPF1, GOLGA6L2, SLC29A3, SGK223, PTGFRN, and FAM186A. Moreover, 7 variants in exons with changes in protein coding are likely of importance in the development of mature cystic teratomas of the ovary, namely PTGFRN, DUSP5, MPP2, PHLDA1, PRR21, GOLGA6L2, and KRTAP4-2. CONCLUSIONS: These genetic alterations may play an important etiological role in teratoma formation. Moreover, novel mutations in DUSP5 and PHLDA1 genes found on whole-exome sequencing may help to explain the characteristics of teratomas.

Treating iPSC-Derived ß Cells with an Anti-CD30 Antibody-Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation.

Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for ß cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody−drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived ß cells (ißs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill ißs nor had an impact on iß identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iß transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived ß cells, potentially providing enhanced safety for iPSC-based ß cell replacement therapy in clinical scenarios.

Inducible motor neuron differentiation of human induced pluripotent stem cells in vivo.

OBJECTIVES: Transplantation of neural progenitor cells (NPCs) derived from human-induced pluripotent stem cells (hiPSCs) is one of the promising treatment strategies for motor neuron diseases (MNDs). However, the inefficiency in committed differentiation of NPCs in vivo limits its application. Here, we tried to establish a potential therapeutic strategy for MNDs by in vivo directional differentiation of hiPSCs engineered with motor neuron (MN) specific transcription factors and Tet-On system. MATERIALS AND METHODS: We engineered hiPSCs with three MN-specific transcription factors and Tet-On system. The engineered cells were directly transplanted into immunodeficient mice through subcutaneous, intra-spinal cord and intracerebroventricular injections. Following doxycycline (Dox) induction, teratoma formation, and motor MN differentiation were evaluated. RESULTS: We generated genetically engineered hiPSCs, in which the expression of Ngn2, Isl1, and Lhx3 was controlled by a drug-inducible transgenic system. These cells showed normal pluripotency and proliferative capacity, and were able to directionally differentiate into mature motor neurons (MNs) and NPCs with high efficiency in spinal cords and cerebral lateral ventricles under the induction of Dox. The grafts showed long-term survival in the recipient mice without formation of teratoma. CONCLUSIONS: The induced mature MNs and NPCs were expected to replace the damaged endogenous MNs directly, and play a role of de novo stem cell stock for long-term neuron damage repair, respectively. Therefore, in vivo directional differentiation of the hiPSCs engineered with MN-specific transcription factors and Tet-On system via Dox induction could be a potential therapeutic strategy for MNDs with high efficacy and safety.

GP2-enriched pancreatic progenitors give rise to functional beta cells in vivo and eliminate the risk of teratoma formation.

Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) can be differentiated into beta-like cells in vitro and in vivo and therefore have therapeutic potential for type 1 diabetes (T1D) treatment. However, the purity of PPs varies across different hPSC lines, differentiation protocols, and laboratories. The uncommitted cells may give rise to non-pancreatic endodermal, mesodermal, or ectodermal derivatives in vivo, hampering the safety of hPSC-derived PPs for clinical applications and their differentiation efficiency in research settings. Recently, proteomics and transcriptomics analyses identified glycoprotein 2 (GP2) as a PP-specific cell surface marker. The GP2-enriched PPs generate higher percentages of beta-like cells in vitro, but their potential in vivo remains to be elucidated. Here, we demonstrate that the GP2-enriched-PPs give rise to all pancreatic cells in vivo, including functional beta-like cells. Remarkably, GP2 enrichment eliminates the risk of teratomas, which establishes GP2 sorting as an effective method for PP purification and safe pancreatic differentiation.

Generation of an integration-free induced pluripotent stem cell line (JTUi004-A) from an otosclerosis patient.

Otosclerosis is caused by abnormal bone remodeling in the middle ear, resulting in progressive hearing loss, dizziness, balance problems, and tinnitus. Previous infection, stress fractures of the bony tissue surrounding the inner ear, immune disorders, and genetic factors are believed to contribute to this disease. Currently, no effective drug treatment for otosclerosis is known. Herein, we generated an induced pluripotent stem cell line from the peripheral blood mononuclear cells of an otosclerosis patient. The cell line exhibited normal morphology, karyotype, and pluripotency marker expression. A teratoma assay revealed successful differentiation into all three germ layers.

The Impact of Surgical Resection and Adjuvant Therapy on Survival in Pediatric Patients with Atypical Teratoid/Rhabdoid Tumor: Systematic Review and Pooled Survival Analysis.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is a rare malignant neoplasm in the pediatric population. ATRT is characterized by rhabdoid cells combined with the loss of either the INI1 (integrase interactor 1) or BRG1 (Brahma-related gene-1) protein. OBJECTIVE: To systematically review and analyze patient and tumor characteristics, prognosis, and impact of treatment on survival in pediatric patients with ATRT confirmed by alterations in INI1 or BRG1. This systematic review is the first to include only pediatric cases of ATRT confirmed with either INI1 or BRG1 alterations. METHODS: MEDLINE was searched using the terms "atypical teratoid/rhabdoid tumor" AND "paediatric/pediatric." Cases were included if confirmed by loss of INI1 or BRG1. The extracted dataset was analyzed using descriptive statistics, log-rank test, and Kaplan-Meier survival analysis via SPSS. RESULTS: A total of 38 articles were included in this study. The average age at diagnosis was 3 years. The most common locations reported are the supratentorial region and cerebral hemispheres. Ninety-three patients were reported to show evidence of dissemination. The average overall survival was 29 months. A significant difference in survival was noted between the tumor location groups, particularly worse outcomes for patients with spinal ATRT (P < 0.001). Extent of resection and adjuvant therapy were significant for survival (χ2 = 10.107, P = 0.018 and χ2 = 20.38, P < 0.0001, respectively). CONCLUSIONS: ATRT of the central nervous system in pediatric populations is a rare neoplasm associated with a poor prognosis in most patients. Future studies should be directed to find a standardized treatment protocol.

Knockdown of Maged1 inhibits cell cycle progression and causes cell death in mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) are characterized by self-renewal and pluripotency and can undergo differentiation into the three germ layers (ectoderm, mesoderm, and endoderm). Melanoma-associated antigen D1 (Maged1), which is expressed in all developing and adult tissues, modulates tissue regeneration and development. In the present study, we examined the expression and function of Maged1 in mESCs. Maged1 protein and mRNA expression increased during mESC differentiation. The pluripotency of mESCs was significantly reduced through extracellular signal-regulated kinase 1/2 phosphorylation upon knockdown of Maged1, and through G1 cell cycle arrest during cell division, resulting in significantly reduced mESC proliferation. Moreover, the diameter of the embryoid bodies was significantly reduced, accompanied by increased levels of ectodermal differentiation markers and decreased levels of mesodermal and endodermal differentiation markers. Maged1-knockdown mESC lines showed significantly reduced teratoma volumes and inhibition of teratoma formation in nude mice. Additionally, we observed increased ectodermal markers but decreased mesodermal and endodermal markers in teratoma tissues. These findings show that Maged1 affects mESC pluripotency, proliferation, cell cycle, and differentiation, thereby contributing to our understanding of the basic molecular biological mechanisms and potential roles of Maged1 as a regulator of various mESC properties.

Spatial molecular profiling of a central nervous system low-grade diffusely infiltrative tumour with INI1 deficiency featuring a high-grade atypical teratoid/rhabdoid tumour component.

We performed spatial epigenetic and transcriptomic analyses of a highly unusual low-grade diffusely infiltrative tumour with INI1 deficiency (CNS LGDIT-INI1), which harboured a high-grade component corresponding to an atypical teratoid/rhabdoid tumour (AT/RT). Methylation profiles of both low-grade and high-grade components yielded high similarity with AT/RTs of the MYC subgroup, whereas RNA expression analyses revealed increased translational activity and MYC pathway activation in the high-grade component. Close follow-up of patients harbouring CNS LGDIT-INI1 is warranted.

The foundational framework of tumors: Gametogenesis, p53, and cancer.

The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.