Addressing Patient Specificity in the Engineering of Tumor Models

Abstract

Cancer treatment is challenged by the heterogeneous nature of cancer, where prognosis depends on tumor type and disease stage, as well as previous treatments. Optimal patient stratification is critical for the development and validation of effective treatments, yet pre-clinical model systems are lacking in the delivery of effective individualized platforms that reflect distinct patient-specific clinical situations. Advances in cancer cell biology, biofabrication, and microengineering technologies have led to the development of more complex in vitro three-dimensional (3D) models to act as drug testing platforms and to elucidate novel cancer mechanisms. Mostly, these strategies have enabled researchers to account for the tumor microenvironment context including tumor-stroma interactions, a key factor of heterogeneity that affects both progression and therapeutic resistance. This is aided by state-of-the-art biomaterials and tissue engineering technologies, coupled with reproducible and high-throughput platforms that enable modeling of relevant physical and chemical factors. Yet, the translation of these models and technologies has been impaired by neglecting to incorporate patient-derived cells or tissues, and largely focusing on immortalized cell lines instead, contributing to drug failure rates. While this is a necessary step to establish and validate new models, a paradigm shift is needed to enable the systematic inclusion of patient-derived materials in the design and use of such models. In this review, we first present an overview of the components responsible for heterogeneity in different tumor microenvironments. Next, we introduce the state-of-the-art of current in vitro 3D cancer models employing patient-derived materials in traditional scaffold-free approaches, followed by novel bioengineered scaffold-based approaches, and further supported by dynamic systems such as bioreactors, microfluidics, and tumor-on-a-chip devices. We critically discuss the challenges and clinical prospects of models that have succeeded in providing clinical relevance and impact, and present emerging concepts of novel cancer model systems that are addressing patient specificity, the next frontier to be tackled by the field.

Stroma-Rich Co-Culture Multicellular Tumor Spheroids as a Tool for Photoactive Drugs Screening

“…Tumor cells, grown as spheroids, more closely resemble in vivo solid tumors presenting physical and physiological barriers to drug action that monolayer cell cultures do not [37,38]. The physiological relevance of the model could be further increased by incorporating multiple cell types (e.g., fibroblasts [39,40,41,42], endothelial cells [39,43], macrophages [44,45,46]).…”

“…Recently 3D co-culture tumor model based on stacked-layer cultures of HNSCC FaDu cells and patient-derived CAFs was configurated and assessed for radiation therapy [36]. However, as discussed recently, the culture of such cells in vitro is challenging due to difficulties in isolation and limited proliferative capacity [38]. In the present study, we developed stroma-rich 3D co-culture HNSCC spheroids consisting of FaDu (human pharynx squamous cell carcinoma) cells and MeWo granular fibroblasts, derived from human melanoma for testing of accumulation, distribution and PDT-mediated toxicity of photoactive drugs.…”

Patient-Derived Organoids for Precision Cancer Immunotherapy

“…It is not that well defined, display batch-to-batch variability and cannot be used for organoid expansion in animal-free or GMP-compliant systems. Synthetic scaffolds with precise ECM composition could overcome these limitations providing well-defined, reproducible, xenogenic-free alternatives (11) (12). Tumor organoids display variable growth rates and reach different sizes (13) (14).…”

Quantifying nanotherapeutics penetration using hydrogel based microsystem as a new 3Din vitroplatform

“…There is an ongoing effort to develop efficient therapeutics for cancer treatment including nano-drugs and nanoparticles, nevertheless, the clinical translation of these therapeutics has to overcome numerous challenges from early stages of development to a successful translation 1,2 . Currently, the standard pipeline for drug development is the following: (1) efficacy tests on 2D in-vitro assays, (2) and on rodent in-vivo models, (3) regulatory toxicity tests on two animal species, (4) clinical trials. However, 2D in-vitro assays do not replicate the 3D-physiological environment encountered by the cells in-vivo.…”