Patient Derived Xenograft
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2021 ◽  
Vol 12 (1) ◽  
Marco Bolis ◽  
Daniela Bossi ◽  
Arianna Vallerga ◽  
Valentina Ceserani ◽  
Manuela Cavalli ◽  

AbstractComprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.

2021 ◽  
Long-ping Wen ◽  
Xiaowan Huang ◽  
Ziyang Cao ◽  
Tao Ding ◽  
Jieying Qian ◽  

Abstract More than half of human malignant tumors harbor TP53 gene mutations, most of which are point mutations within the DNA-binding domain of TP53, resulting in mutant p53 (mutp53) protein stabilization and accumulation in the cell and enhanced tumor progression. Depletion of mutp53 through the autophagy or proteasome pathway is considered the most direct strategy to target mutp53 for tumor treatment. However, due to the lack of specific autophagy receptors and the insufficient level of autophagy in tumor cells, targeted degradation of mutp53 by nanomaterials via the autophagy pathway has not been reported. Here, we propose a type of "nanoreceptors" (denoted NRs) that mimics selective autophagy receptors and develop a new platform for targeted degradation of mutp53. The NRs specifically bind mutp53 in tumor cells via mutp53-binding peptide (MBP). In addition, the level of cell autophagy is greatly increased due to the incorporated of cationic lipid. As a result, the NRs effectively degrade mutp53 through the autophagy pathway with complete autophagic flux. The knockout of ATG5, an essential autophagy-related gene, significantly inhibited the NRs-induced degradation of mutp53, demonstrating the critical role of autophagy in this effect. Subsequently, the degradation of mutp53 by the NRs abrogated mutp53-conferred gain-of-function (GOF) phenotypes, including enhanced cell proliferation and cell migration and reduced sensitivity to cisplatin (CDDP). Last, Pt(IV)-loaded NRs (NRs/Pt, consisting of Pt(IV) prodrug encapsulated in the NRs) showed outstanding synergistic antitumor effects in an ES-2 ovarian cancer model and a patient-derived xenograft (PDX) ovarian cancer model. Collectively, our study suggests the use of NRs/Pt as a new biomimetic nanoplatform for regulating autophagy, providing new ideas for precise tumor treatments that target mutp53.

Roger S. Smith ◽  
Igor Odintsov ◽  
Zebing Liu ◽  
Allan Jo-Weng Lui ◽  
Takuo Hayashi ◽  

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered pre-clinical therapeutic studies in this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft (PDX) model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small molecule inhibitors (afatinib, neratinib), or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT.

2021 ◽  
Vol 19 (4) ◽  
pp. 197-222
Jung Woo Lee ◽  
Jia Kim ◽  
Youngjae Shin ◽  
Byung Hoon Chi ◽  
Jung Hoon Kim ◽  

The heterogeneity of cancer makes it difficult to predict the prognosis of treatment. There is still a lack of preclinical model systems that reflect the clinical characteristics of patients who have heterogenetic tumors. Advances in 3-dimentional (3D) cell culture are leading to discoveries that occur in the development and progression of cancer that has not been known. There are many models including patient-derived xenograft, patient-derived organoid and spheroid, patient-derived explant, scaffold-based model, and system-based model. Each 3D model has its strengths and limitations. One model cannot answer every question, so it seems most reasonable to approach multiple models when studying cancer heterogeneity. Hopefully, 3D tumor modeling will make tremendous progress on this path by fusion of innovative biomaterials and advanced modeling techniques that can partially mimic the heterogeneous environment of real tumors.

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5964
Anilkumar Gopalakrishnapillai ◽  
Colin E. Correnti ◽  
Kristina Pilat ◽  
Ida Lin ◽  
Man Kid Chan ◽  

Advances in the treatment of pediatric AML have been modest over the past four decades. Despite maximally intensive therapy, approximately 40% of patients will relapse. Novel targeted therapies are needed to improve outcomes. We identified mesothelin (MSLN), a well-validated target overexpressed in some adult malignancies, to be highly expressed on the leukemic cell surface in a subset of pediatric AML patients. The lack of expression on normal bone marrow cells makes MSLN a viable target for immunotherapies such as T-cell engaging bispecific antibodies (BsAbs) that combine two distinct antibody-variable regions into a single molecule targeting a cancer-specific antigen and the T-cell co-receptor CD3. Using antibody single-chain variable region (scFv) sequences derived from amatuximab-recognizing MSLN, and from either blinatumomab or AMG330 targeting CD3, we engineered and expressed two MSLN/CD3-targeting BsAbs: MSLNAMA-CD3L2K and MSLNAMA-CD3AMG, respectively. Both BsAbs promoted T-cell activation and reduced leukemic burden in MV4;11:MSLN xenografted mice, but not in those transplanted with MSLN-negative parental MV4;11 cells. MSLNAMA-CD3AMG induced complete remission in NTPL-146 and DF-5 patient-derived xenograft models. These data validate the in vivo efficacy and specificity of MSLN-targeting BsAbs. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients.

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5962
Chiao-Yun Lin ◽  
Ren-Chin Wu ◽  
Chen-Yang Huang ◽  
Chyong-Huey Lai ◽  
An-Shine Chao ◽  

Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.

2021 ◽  
Ella N Perrault ◽  
Jack M Shireman ◽  
Eunus S Ali ◽  
Isabelle Preddy ◽  
Peiyu Lin ◽  

Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies have examined primary and recurrent GBM tumors, but it is difficult to study tumor evolution during therapy where resistance develops. To investigate this, we performed an in vivo single-cell RNA sequencing screen in a patient-derived xenograft (PDX) model. Primary GBM was modeled by mice treated with DMSO control, recurrent GBM was modeled by mice treated with temozolomide (TMZ), and during therapy GBM was modeled by mice euthanized after two of five TMZ treatments. Our analysis revealed the cellular population present during therapy to be distinct from primary and recurrent GBM. We found the Ribonucleotide Reductase gene family to exhibit a unique signature in our data due to an observed subunit switch to favor RRM2 during therapy. GBM cells were shown to rely on RRM2 during therapy causing RRM2-knockdown (KD) cells to be TMZ-sensitive. Using targeted metabolomics, we found RRM2-KDs to produce less dGTP and dCTP than control cells in response to TMZ (p<0.0001). Supplementing RRM2-KDs with deoxycytidine and deoxyguanosine rescued TMZ-sensitivity, suggesting an RRM2-driven mechanism of chemoresistance, established by regulating the production of these nucleotides. In vivo, tumor-bearing mice treated with the RRM2-inhibitor, Triapine, in combination with TMZ, survived longer than mice treated with TMZ alone (p<0.01), indicating promising clinical opportunities in targeting RRM2. Our data present a novel understanding of RRM2 activity, and its alteration during therapeutic stress as response to TMZ-induced DNA damage.

2021 ◽  
Zhonglin Wang ◽  
Shuqin Li ◽  
Feng Xu ◽  
Jingyue Fu ◽  
Jie Sun ◽  

Abstract Background: Breast cancer is notorious for its increasing incidence for decades. Ascending evidence has demonstrated that translocase of inner mitochondrial membrane (TIMM) proteins play vital roles in progression of several types of human cancer. However, the biological behaviors and molecular mechanisms of TIMM8A in breast cancer remain not fully illustrated.Methods: Pan-cancer analysis was firstly performed for TIMM8A’s expression and prognosis by Oncomine database. Subsequently, TIMM8A-related noncoding RNAs (ncRNAs) were identified by a series of bioinformatics analyses and dual-luciferase reporter assay, including expression analysis, correlation analysis, and survival analysis. Moreover, the effect of TIMM8A on breast cancer proliferation and apoptosis was evaluated in vitro by CCK-8 assays, colony formation assays and Western blot assays and the in vivo effect was revealed through a patient-derived xenograft mouse model.Results: We found that TIMM8A showed higher expression level in breast cancer and the higher TIMM8A mRNA expression group had a poorer prognosis than the lower TIMM8A group. hsa-circ-0107314/hsa-circ-0021867/hsa-circ-0122013 might be the three most potential upstream circRNAs of hsa-miR-34c-5p/hsa-miR-449a-TIMM8A axis in breast cancer. TIMM8A promotes proliferation of breast cancer cells in vitro and tumor growth in vivo.Conclusion: Our results confirmed that ncRNAs-mediated upregulation of TIMM8A correlated with poor prognosis and act as an oncogene in breast cancer.

2021 ◽  
Vol 19 (1) ◽  
Sheng Zheng ◽  
Jiafeng Wang ◽  
Ning Ding ◽  
Wenwen Chen ◽  
Hongda Chen ◽  

Abstract Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form [email protected] nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. [email protected] treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of [email protected] to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract

Blood ◽  
2021 ◽  
Wenbin Zhong ◽  
Xiuye Cao ◽  
Guoping Pan ◽  
Qun Niu ◽  
Xiaoqin Feng ◽  

Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. Here we report that ORP4L is expressed in ATL cells but not normal T-cells. ORP4L ablation completely blocks T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice while engineering ORP4L expression in T-cells results in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L for the initiation of T-cell leukemogenesis. For molecular insight, loss of miR-31 caused by HTLV-1 induces ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation, NF-κB-dependent p53 inactivation induced pro-oncogenes expression and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cells deterioration by HTLV-1 that can be therapeutically targeted.

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