Addressing Modern Diagnostic Pathology for Patient-Derived Soft Tissue Sarcosphere Models in the Era of Functional Precision Oncology

Chen, Yanjiang; Herzog, Marius; Pliego-Mendieta, Alicia; Bühler, Marco; Harnisch, Kim Jannis; Haberecker, Martina; Arnold, Fabian; Planas-Paz, Lara; Pauli, Chantal

doi:10.1016/j.labinv.2022.100039

Cited by 3 publications

(13 citation statements)

References 30 publications

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“…To investigate novel therapeutic strategies for sarcoma with HRDness traits, we first established genomically and transcriptomically characterized patient-derived ex vivo sarcoma cell models. All cell models faithfully recapitulated the molecular alterations from their corresponding tumor of origin (Fig 5A and B;Bangerter et al, 2022;Chen et al, 2022;Pauli et al, 2022). We molecularly characterized four human MFS cell models, namely NMFH1, OH931, PM197, USZ-21_MFS2, and one UPS cell model (USZ-21_UPS1) by whole-genome sequencing.…”

Section: Genomic and Transcriptomic Characterization Of Patient-deriv...mentioning

confidence: 71%

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Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRD high sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

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Section: Genomic and Transcriptomic Characterization Of Patient-deriv...mentioning

confidence: 71%

“…Patient‐derived sarcoma cell models were authenticated and established as previously described (Bangerter et al , 2022 ; Chen et al , 2022 ) from both male and female patients to avoid gender bias. Informed consent was obtained from all subjects.…”

Section: Methodsmentioning

confidence: 99%

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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“…Here, we discussed various techniques that allow the formation of organoids, including scaffold-free [29][30][31], scaffold-based [25,[32][33][34][35], and xenograft-based [36,37] methods (Figure 2). Scaffold-free techniques involve the use of specialized culture plates or dishes that facilitate the self-assembly of cells into three-dimensional structures without the need for a physical scaffold.…”

Section: Recapitulating Tumor Heterogeneity and Complexity In Pdsosmentioning

confidence: 99%

“…For example, studies have demonstrated that cell expansion and the use of immortalized cell lines can lead to genetic and functional changes, which can significantly affect the reliability and accuracy of in vitro treatment responses [52,53]. Moreover, specialized media used for culturing PDSOs are often supplemented with growth factors, cytokines, and other components that are nonclinical in nature (Table 1) [29,30,33]. These factors have the potential to influence cellular responses such as proliferation, differentiation, and drug resistance, thereby impacting the accuracy of patient outcomes [29].…”

mentioning

confidence: 99%

“…Moreover, specialized media used for culturing PDSOs are often supplemented with growth factors, cytokines, and other components that are nonclinical in nature (Table 1) [29,30,33]. These factors have the potential to influence cellular responses such as proliferation, differentiation, and drug resistance, thereby impacting the accuracy of patient outcomes [29]. In the past, the effects of these factors, particularly in functional assays like drug screening, were often overlooked by researchers.…”

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confidence: 99%

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Patient-Derived Organoids as a Promising Tool for Multimodal Management of Sarcomas

Xu,

Tan,

Guo

2023

Cancers

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The management of sarcomas, a diverse group of cancers arising from connective tissues, presents significant challenges due to their heterogeneity and limited treatment options. Patient-derived sarcoma organoids (PDSOs) have emerged as a promising tool in the multimodal management of sarcomas, offering unprecedented opportunities for personalized medicine and improved treatment strategies. This review aims to explore the potential of PDSOs as a promising tool for multimodal management of sarcomas. We discuss the establishment and characterization of PDSOs, which realistically recapitulate the complexity and heterogeneity of the original tumor, providing a platform for genetic and molecular fidelity, histological resemblance, and functional characterization. Additionally, we discuss the applications of PDSOs in pathological and genetic evaluation, treatment screening and development, and personalized multimodal management. One significant advancement of PDSOs lies in their ability to guide personalized treatment decisions, enabling clinicians to assess the response and efficacy of different therapies in a patient-specific manner. Through continued research and development, PDSOs hold the potential to revolutionize sarcoma management and drive advancements in personalized medicine, biomarker discovery, preclinical modeling, and therapy optimization. The integration of PDSOs into clinical practice can ultimately improve patient outcomes and significantly impact the field of sarcoma treatment.

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Modeling Myxofibrosarcoma: Where Do We Stand and What Is Missing?

Lucarelli,

De Vita,

Bellotti

et al. 2023

Cancers

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Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body’s connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the fifth decade of life. Considering the ongoing trend of increasing lifespans across many nations, MFS is likely to become the most common musculoskeletal sarcoma in the future. Although MFS patients have a lower risk of developing distant metastases compared with other STS cases, MFS is characterized by a high frequency of local recurrence. Notably, in 40–60% of the patients where the tumor recurs, it does so multiple times. Consequently, patients may undergo multiple local surgeries, removing the risk of potential amputation. Furthermore, because the tumor relapses generally have a higher grade, they exhibit a decreased response to radio and chemotherapy and an increased tendency to form metastases. Thus, a better understanding of MFS is required, and improved therapeutic options must be developed. Historically, preclinical models for other types of tumors have been instrumental in obtaining a better understanding of tumor development and in testing new therapeutic approaches. However, few MFS models are currently available. In this review, we will describe the MFS models available and will provide insights into the advantages and constraints of each model.

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Addressing Modern Diagnostic Pathology for Patient-Derived Soft Tissue Sarcosphere Models in the Era of Functional Precision Oncology

Cited by 3 publications

References 30 publications

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Patient-Derived Organoids as a Promising Tool for Multimodal Management of Sarcomas

Modeling Myxofibrosarcoma: Where Do We Stand and What Is Missing?

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