Three-Dimensional Patient-Derived In Vitro Sarcoma Models: Promising Tools for Improving Clinical Tumor Management

Abstract

Over the past decade, the development of new targeted therapeutics directed against specific molecular pathways involved in tumor cell proliferation and survival has allowed an essential improvement in carcinoma treatment. Unfortunately, the scenario is different for sarcomas, a group of malignant neoplasms originating from mesenchymal cells, for which the main therapeutic approach still consists in the combination of surgery, chemotherapy, and radiation therapy. The lack of innovative approaches in sarcoma treatment stems from the high degree of heterogeneity of this tumor type, with more that 70 different histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Currently, molecular therapies are available mainly for the treatment of gastrointestinal stromal tumor, a soft-tissue malignancy characterized by an activating mutation of the tyrosine kinase KIT. Since the first application of this approach, a strong effort has been made to understand sarcoma molecular alterations that can be potential targets for therapy. The low incidence combined with the high level of histopathological heterogeneity makes the development of clinical trials for sarcomas very challenging. For this reason, preclinical studies are needed to better understand tumor biology with the aim to develop new targeted therapeutics. Currently, these studies are mainly based on in vitro testing, since cell lines, and in particular patient-derived models, represent a reliable and easy to handle tool for investigation. In the present review, we summarize the most important models currently available in the field, focusing in particular on the three-dimensional spheroid/organoid model. This innovative approach for studying tumor biology better represents tissue architecture and cell–cell as well as cell–microenvironment crosstalk, which are fundamental steps for tumor cell proliferation and survival.

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…Nevertheless, the precise identity of the cell at the origin of the tumor remains unknown. Evidence supports the idea of an origin of OS in mesenchymal stem/stromal cells (MSCs) and/or in more committed osteoblastic precursors [2,3]. Since the introduction of chemotherapies to treat OS the late 70s, patients diagnosed with OS receive a neo-adjuvant treatment followed by a post-surgery adjuvant therapy with a cocktail of chemotherapies, i.e., high-dose methotrexate (12 g/m 2 ), etoposide, and ifosfamide for children and young adults (<25 years) in the French OS2006/sarcome-09 study [4], or other protocols combining doxorubicin, cisplatin, and ifosfamide with or without high-dose methotrexate [5][6][7].…”

Sarcoma Spheroids and Organoids—Promising Tools in the Era of Personalized Medicine

“…Studies have demonstrated that ultra-low-attachment microplates generate organoids of larger size (300–400 μm), one per well, in a few days (three days if at least 5 × 10 3 cells are plated), but they were never tested in sarcoma [ 43 ]. Organoids retain the structure, morphology, stromal composition, genetic mutations, and heterogeneity of the original tumor [ 44 ]. Furthermore, when organoids are transplanted into mice, they form carcinomas that histologically resemble the tumor of origin [ 44 , 45 ].…”

“…Organoids retain the structure, morphology, stromal composition, genetic mutations, and heterogeneity of the original tumor [ 44 ]. Furthermore, when organoids are transplanted into mice, they form carcinomas that histologically resemble the tumor of origin [ 44 , 45 ]. The opportunity to reproduce in vitro and within a few days both the complex structure of the microenvironment and the chromosome aneuploidies characteristic of individual sarcomas is of great interest, mainly because the environment changes the tumor’s cellular responses to drugs.…”

From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

“… Huang et al (2014) have published similar numbers. As increasing tumor sequencing data becomes available from large cohorts within the framework of multinational sequencing projects such as the ICGC and the Cancer Genome Atlas, researchers have identified more molecular subtypes of tumors ( Curtis et al, 2012 ; Guinney et al, 2015 ; Gaebler et al, 2017 ). The use of cetuximab-based therapy in RAS wildtype colorectal cancers ( Khambata-Ford et al, 2007 ) and the use of ALK kinase inhibitors in EML4-ALK-positive NSCLC ( Shaw et al, 2013 ) are two successful examples.…”