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Cancer is a heterogeneous disease. Each individual tumor is unique and characterized by structural, cellular, genetic and molecular features. Therefore, patient-derived cancer models are indispensable tools in cancer research and have been actively introduced into the healthcare system. For instance, patient-derived models provide a good reproducibility of susceptibility and resistance of cancer cells against drugs, allowing personalized therapy for patients. In this article, we review the advantages and disadvantages of the following patient-derived models of cancer: (1) PDC—patient-derived cell culture, (2) PDS—patient-derived spheroids and PDO—patient-derived organoids, (3) PDTSC—patient-derived tissue slice cultures, (4) PDX—patient-derived xenografts, humanized PDX, as well as PDXC—PDX-derived cell cultures and PDXO—PDX-derived organoids. We also provide an overview of current clinical investigations and new developments in the area of patient-derived cancer models. Moreover, attention is paid to databases of patient-derived cancer models, which are collected in specialized repositories. We believe that the widespread use of patient-derived cancer models will improve our knowledge in cancer cell biology and contribute to the development of more effective personalized cancer treatment strategies.

Background Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy. Methods We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2 –amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer. Results LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2 -amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2 -amplified patient derived tumor xenografts from three metastatic colorectal cancer patients. Conclusions These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2 -amplified colorectal cancer.

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre‐clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient‐derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre‐clinical evaluation of onco‐immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies. Establishing predictive pre‐clinical models leads toward more accurate and practical immunotherapeutic development. Humanized mice (HM) provide a suitable platform to discern human‐specific disease pathogenesis and evaluate an array of novel therapeutics. This review discusses recent progresses in the production and deployment of HM in the study of cancer immunotherapy.

Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Despite current aggressive treatment regimens, the prognosis for high‐risk NB patients remains poor, with the survival of less than 40%. Amplification/stabilization of MYCN oncogene, in NB is associated with a high risk of recurrence. Thus, there is an urgent need for novel therapeutics. The deregulated expression of microRNA (miR) is reported in NB; nonetheless, its effect on MYCN regulation is poorly understood. First, we identified that miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p (hereafter miR‐15a, miR‐15b or miR‐16) were down‐regulated in patient‐derived xenografts (PDX) with high MYCN expression. MiR targeting sequences on MYCN mRNA were predicted using online databases such as TargetScan and miR database. The R2 database, containing 105 NB patients, showed an inverse correlation between MYCN mRNA and deleted in lymphocytic leukemia (DLEU) 2, a host gene of miR‐15. Moreover, overexpression of miR‐15a, miR‐15b or miR‐16 significantly reduced the levels of MYCN mRNA and N‐Myc protein. Conversely, inhibiting miR dramatically enhanced MYCN mRNA and N‐Myc protein levels, as well as increasing mRNA half‐life in NB cells. By performing immunoprecipitation assays of argonaute‐2 (Ago2), a core component of the RNA‐induced silencing complex, we showed that miR‐15a, miR‐15b and miR‐16 interact with MYCN mRNA. Luciferase reporter assays showed that miR‐15a, miR‐15b and miR‐16 bind with 3’UTR of MYCN mRNA, resulting in MYCN suppression. Moreover, induced expression of miR‐15a, miR‐15b and miR‐16 significantly reduced the proliferation, migration, and invasion of NB cells. Finally, transplanting miR‐15a‐, miR‐15b‐ and miR‐16‐expressing NB cells into NSG mice repressed tumor formation and MYCN expression. These data suggest that miR‐15a, miR‐15b and miR‐16 exert a tumor‐suppressive function in NB by targeting MYCN. Therefore, these miRs could be considered as potential targets for NB treatment. A model summarizing how miR‐15a, miR‐15b, and miR‐16 suppress tumor progression in neuroblastoma by targeting MYCN. When miRs are overexpressed, argonaute‐2‐mediated interaction of miR with MYCN mRNA increases, followed by degradation of MYCN, leading to neuroblastoma regression.

Patient‐derived xenograft (PDX) models provide a robust preclinical platform that preserves the genetic and phenotypic heterogeneity of patient tumors while mirroring their tumor genetic characteristics, which retain malignant cells and the tumor pathological structure, making them valuable for studying tumor progression and developing anticancer therapies. This review outlines the establishment of PDX models and their applications in tumor research by comparing their attributes and limitations with other experimental models. It explores the use of PDX models in understanding tumor progression mechanisms, resistance mechanisms, and treatment strategies, including radiotherapy, chemotherapy, targeted therapy, immunotherapy, nanotherapy, cell therapy, antibody‐drug conjugates, and combination therapy. Integration of PDX models with multi‐omics technologies is also discussed, along with their application in co‐clinical and clinical studies. Notably, this review covers approximately 30 cancer types and aims to guide future cancer research.

Cancer is a major stress for public well‐being and is the most dreadful disease. The models used in the discovery of cancer treatment are continuously changing and extending toward advanced preclinical studies. Cancer models are either naturally existing or artificially prepared experimental systems that show similar features with human tumors though the heterogeneous nature of the tumor is very familiar. The choice of the most fitting model to best reflect the given tumor system is one of the real difficulties for cancer examination. Therefore, vast studies have been conducted on the cancer models for developing a better understanding of cancer invasion, progression, and early detection. These models give an insight into cancer etiology, molecular basis, host tumor interaction, the role of microenvironment, and tumor heterogeneity in tumor metastasis. These models are also used to predict novel cancer markers, targeted therapies, and are extremely helpful in drug development. In this review, the potential of cancer models to be used as a platform for drug screening and therapeutic discoveries are highlighted. Although none of the cancer models is regarded as ideal because each is associated with essential caveats that restraint its application yet by bridging the gap between preliminary cancer research and translational medicine. However, they promise a brighter future for cancer treatment. In vitro and in vivo Animal models have been extensively used in cancer research. At present omics data and computational models are in practice. Each model has it own pros and cons.

Colorectal cancer (CRC) is a complex and heterogeneous disease, characterized by dismal prognosis and low survival rate in the advanced (metastatic) stage. During the last decade, the establishment of novel preclinical models, leading to the generation of translational discovery and validation platforms, has opened up a new scenario for the clinical practice of CRC patients. To bridge the results developed at the bench with the medical decision process, the ideal model should be easily scalable, reliable to predict treatment responses, and flexibly adapted for various applications in the research. As such, the improved benefit of novel therapies being tested initially on valuable and reproducible preclinical models would lie in personalized treatment recommendations based on the biology and genomics of the patient’s tumor with the overall aim to avoid overtreatment and unnecessary toxicity. In this review, we summarize different in vitro and in vivo models, which proved efficacy in detection of novel CRC culprits and shed light into the biology and therapy of this complex disease. Even though cell lines and patient-derived xenografts remain the mainstay of colorectal cancer research, the field has been confidently shifting to the use of organoids as the most relevant preclinical model. Prioritization of organoids is supported by increasing body of evidence that these represent excellent tools worth further therapeutic explorations. In addition, novel preclinical models such as zebrafish avatars are emerging as useful tools for pharmacological interrogation. Finally, all available models represent complementary tools that can be utilized for precision medicine applications.

As membrane‐bound extracellular vesicles, exosomes have targeting ability for specific cell types, and the cellular environment strongly impacts their content and uptake efficiency. Inspired by these natural properties, the impacts of various cellular stress conditions on the uptake efficiency of tumor iterated exosomes are evaluated, and low‐pH treatment caused increased uptake efficiency and retained cell‐type specificity is found. Lipidomics analyses and molecular dynamics simulations reveal a glycerolipid self‐aggregation‐based mechanism for the enhanced homologous uptake. Furthermore, these low‐pH reprogrammed exosomes are developed into a smart drug delivery platform, which is capable of specifically targeting tumor cells and selectively releasing diverse chemodrugs in response to the exosome rupture by the near‐infrared irradiance‐triggered burst of reactive oxygen species. This platform exerts safe and enhanced antitumor effects demonstrated by multiple model mice experiments. These results open a new avenue to reprogram exosomes for smart drug delivery and potentially personalized therapy against their homologous tumor. Tumor exosomes treated by low‐pH condition can enhance their uptake efficiency and retain cell‐type specificity for their parent cells based on a glycerolipid self‐aggregation‐based mechanism. They are developed as a smart drug delivery platform, specifically targeting tumor cells and selectively releasing diverse chemodrugs in response to the near‐infrared irradiance, to achieve safe and enhanced antitumor effects.

The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF V600E metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF V600E , we identified a new activating insertion in MEK1 . This MEK1 T55delins RT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases. A new 3‐bp insertion in the MEK1 gene (MEK1 T55delinsRT ) confers resistance to vemurafenib. The MEK1 T55delinsRT mutation can be traced back to a fraction of the pre‐treatment tumor. Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies.

Patient‐derived xenografts (PDXs) can be improved by implantation of a humanized niche. Nevertheless, the overall complexity of the current protocols, as well as the use of specific biomaterials and procedures, limits the wider adoption of this approach. Here, we identify the essential minimum steps required to create the humanized scaffolds and achieve successful acute myeloid leukemia (AML) engraftment. We compared seven biomaterials, which included both published and custom‐designed materials. The highest level of bone marrow niche was achieved with extracellular matrix gels and custom collagen fiber, both of which allowed for a simple non‐surgical implantation. The biomaterial selection did not influence the following AML infiltration. Regarding xenotransplantation, standard intravenous administration produced the most robust engraftment, even for two out of four otherwise non‐engrafting AML samples. In contrast, direct intra‐scaffold xenotransplantation did not offer any advantage. In summary, we demonstrate that the combination of an injectable biomaterial for scaffold creation plus an intravenous route for AML xenotransplantation provide the most convenient and robust approach to produce AML PDX using a humanized niche. Patient‐derived xenografts (PDXs) can be improved by implantation of a humanized niche. We tested different biomaterials and approaches, and demonstrate that the combination of an injectable biomaterial for scaffold creation plus an intravenous route for acute myeloid leukemia (AML) xenotransplantation provide the most convenient and robust approach to produce AML PDXs using a humanized niche, even for otherwise non‐engrafting samples.