Patient-derived xenografts (PDXs) as model systems for human cancer

Invrea, Federica; Rovito, Roberta; Torchiaro, Erica; Petti, Consalvo; Isella, Claudio; Medico, Enzo

doi:10.1016/j.copbio.2020.01.003

Cited by 51 publications

(36 citation statements)

References 46 publications

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“…The results demonstrated that circRHBDD1 was closely associated with the augmented glycolysis and glutaminolysis of HCC cells. Recapitulating the principal morphologic and genetic features of the original tumors, PDX models represent powerful resources for evaluating the in vivo effect of novel therapeutic strategies [32]. In consistence with the in vitro results, we constructed PDX mouse models and veri ed the tumor-promoting effects of circRHBDD1 in vivo.…”

Section: Discussionmentioning

confidence: 99%

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Cai

Chen

Zhang

et al. 2021

Preprint

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Background Metabolic rewiring of cancer cells reshapes the tumor microenvironment, thereby restricting the response to immunotherapy. Circular RNAs (circRNAs) can influence various cellular processes and have been implicated in hepatocellular carcinoma (HCC). Here, we investigated the role of a novel circRNA circRHBDD1 in HCC metabolic transformation and immunotherapy resistance. Methods CircRNA sequencing was performed to determine the differentially expressed circRNA profile in HCC. RT-qPCR and in situ hybridization were used to verify the dysregulation of circRHBDD1 in two independent HCC cohorts. Univariate and multivariate survival analyses were employed to assess the prognostic significance of circRHBDD1. Loss- and gain-of-function approaches were adopted to evaluate the effects of circRHBDD1 on glycolysis and glutaminolysis. Patient-derived xenograft models were used for in vivo evaluation. RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescence in situ hybridization, polysome profiling, and meRIP assays were utilized to explore the molecular mechanisms of circRHBDD1 in HCC. Results We found that circRHBDD1 was significantly upregulated in HCC and associated with unfavorable clinicopathological characteristics and poor survival outcomes. In vitro and in vivo experiments showed that circRHBDD1 facilitated HCC glycolysis and glutaminolysis. Mechanistic studies revealed that circRHBDD1 could recruit YTHDF1 to PIK3R1 mRNA and augment PIK3R1 translation in an m6A-dependent manner, leading to activation of the PI3K/AKT signaling. EIF4A3-mediated exon back-splicing contributed to the upregulation of circRHBDD1. Moreover, targeting of circRHBDD1 was able to improve anti-PD-1 therapy resulting in prolonged survival. Conclusion We identified that the circRHBDD1/YTHDF1/PIK3R1 axis was crucial to metabolic reprogramming of HCC. Suppression of circRHBDD1 could potentially sensitize HCC cells to anti-PD-1 therapy.

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Section: Discussionmentioning

confidence: 99%

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Cai

Chen

Zhang

et al. 2021

Preprint

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“…Despite the breakthrough accomplishments of the MIS (KI) TRG6 mouse described above, this xenograft model of human myeloma is still limited compared to well-established PDX (patient derived xenograft) models of solid cancer ( 193 ) and emerging PDX models of lymphoma ( 194 ). Biological limitations of MIS (KI) TRG6 and the parental strain, MIS (KI) TRG, include proclivity to anemia and quick exhaustion of human grafts after cell or tissue transfer ( 195 ).…”

Section: Research Gaps and Future Directionsmentioning

confidence: 99%

Laboratory Mice – A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma

et al. 2021

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Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

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“…However, given a large number of approved and candidate drugs, it is not feasible to compare all immunotherapy agents in a clinical setting. Therefore, various experimental ex vivo models have been developed to study combination treatment, including classical 2D cell culture models, tumor spheroids and organoids, and patient-derived xenografts 15 – 18 . Among these models, conventional 2D cell culture cannot effectively recapitulate the complexity of cellular interactions and mimic the in vivo TME.…”

Section: Introductionmentioning

confidence: 99%

3D tumor spheroid microarray for high-throughput, high-content natural killer cell-mediated cytotoxicity

Gopal

Kwon

Ku³

et al. 2021

Commun Biol

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Immunotherapy has emerged as a promising approach to treating several forms of cancer. Use of immune cells, such as natural killer (NK) cells, along with small molecule drugs and antibodies through antibody dependent cell-mediated cytotoxicity (ADCC) has been investigated as a potential combination therapy for some difficult to treat solid tumors. Nevertheless, there remains a need to develop tools that support co-culture of target cancer cells and effector immune cells in a contextually relevant three-dimensional (3D) environment to provide a rapid means to screen for and optimize ADCC-drug combinations. To that end, here we have developed a high throughput 330 micropillar-microwell sandwich platform that enables 3D co-culture of NK92-CD16 cells with pancreatic (MiaPaCa-2) and breast cancer cell lines (MCF-7 and MDA-MB-231). The platform successfully mimicked hypoxic conditions found in a tumor microenvironment and was used to demonstrate NK-cell mediated cell cytotoxicity in combination with two monoclonal antibodies; Trastuzumab and Atezolizumab. The platform was also used to show dose response behavior of target cancer cells with reduced EC50 values for paclitaxel (an anti-cancer chemotherapeutic) when treated with both NK cells and antibody. Such a platform may be used to develop more personalized cancer therapies using patient-derived cancer cells.

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Patient-derived xenografts (PDXs) as model systems for human cancer

Cited by 51 publications

References 46 publications

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Laboratory Mice – A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma

3D tumor spheroid microarray for high-throughput, high-content natural killer cell-mediated cytotoxicity

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