RESUMEN
Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing-based strategy to generate primary, orthotopic, and driver-defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid-initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high-throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Endometriales , Femenino , Animales , Ratones , Humanos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Mutación/genética , Modelos AnimalesRESUMEN
Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we generate a series of primary GC models in mice with genome-edited gastric organoids, which elucidate the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC. Further, we find that the orthotopic GC, but not the subcutaneous GC even with the same genetic drivers, display remote metastasis, suggesting critical roles of the microenvironment in GC metastasis. Through single-cell RNA-seq analyses and functional studies, we show that the interaction between fibronectin 1 on stomach-specific macrophages and integrin a6ß4 on GC cells promotes remote metastases. Taken together, our studies propose a strategy to model GC and dissect the genetic and microenvironmental factors driving the full-range gastric tumorigenesis.
Asunto(s)
Fibronectinas , Neoplasias Gástricas , Ratones , Animales , Línea Celular Tumoral , Carcinogénesis/genética , Carcinogénesis/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Transformación Celular Neoplásica , Integrinas , Microambiente TumoralRESUMEN
Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.
Asunto(s)
ADN Metiltransferasa 3A , N-Metiltransferasa de Histona-Lisina , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Animales , ADN/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN/genética , ADN Metiltransferasa 3A/genética , Metilasas de Modificación del ADN/genética , Epigénesis Genética/genética , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metiltransferasas/genética , Ratones , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/secundarioRESUMEN
The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer. Here, we report that esophageal squamous cell carcinoma (ESCC) cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells, which we term as confused cell identity (CCI). CCI is an independent prognostic marker associated with poor prognosis in ESCC. Further, we identify tropomyosin 4 (TPM4) as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo. And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway. Thus, our study suggests an unrecognized feature of ESCC cells, which might be of value for clinic prognosis and potential interference.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , HumanosRESUMEN
By employing tert-butyl nitrite as both nitrogen source and oxidant, the trifluoromethyloximation of alkenes proceeds smoothly in a free-radical process. The developed difunctionalization reaction enables practical and efficient synthesis of a wide range of α-CF3 ketoximes in moderate yields with excellent regioselectivity. This method features the use of readily available and stable alkenes as substrates and inexpensive CF3 SO2 Na as a CF3 reagent, no involvement of transition metals or external oxidant, and room-temperature conditions. Moreover, a scale-up of the reaction, further transformation of the products into various valuable CF3 -containing compounds, and removal of the trifluoromethyl group are readily achieved.