Multicellular spheroid based on a triple co-culture: A novel 3D model to mimic pancreatic tumor complexity

Abstract

Pancreatic tumor microenvironment is characterized by abundant fibrosis and aberrant vasculature. Aiming to reproduce in vitro these features, cancer cells have been already co-cultured with fibroblasts or endothelial cells separately but the integration of both these essential components of the pancreatic tumor microenvironment in a unique system, although urgently needed, was still missing. In this study, we successfully integrated cellular and acellular microenvironment components (i.e., fibroblasts, endothelial cells, fibronectin) in a hetero-type scaffold-free multicellular tumor spheroid. This new 3D triple co-culture model closely mimicked the resistance to treatments observed in vivo, resulting in a reduction of cancer cell sensitivity to the anticancer treatment.

Chemoradiotherapy screening in a novel biomimetic polymer based pancreatic cancer model

“…7,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] However, most studies focus on the development of the actual 3D model and, to the best of our knowledge, there are very limited 3D studies on PDAC treatment screening (chemotherapy and radiotherapy) with most studies conducted in 3D spheroids (cell aggregates). 14,32,[34][35][36][49][50][51][52] Generally, these studies report a higher resistance of PDAC to treatment in 3D when compared to 2D cultures, a trend which is in closer alignment with in vivo studies. 34,49,52 For example, Longati et al (2013) studied the impact of the chemotherapeutic drug Gemcitabine (GEM, 0-1 mM) on the viability of PDAC spheroids and observed a higher resistance of the spheroids to the drug, as compared to a 2D culture.…”

“…The short culture duration is a key bottleneck for treatment related studies. More specically, as described above, most treatment studies in spheroids have been monitored for a maximum of 7 days, 32,34,35,52 which is signicantly shorter in comparison to patients' treatment time-frame and to animal models which are usually assessed over a time frame of several weeks. 2,11,[14][15][16][17][55][56][57] Furthermore, in vitro models that allow long term post-treatment monitoring would enable the conduction of fractionated radiation screening wherein radiotherapeutic treatment is provided to the patients in serial smaller dosages over a specic time interval to minimise radiation related side effects.…”

Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment

“…In order to more closely mimic the TME, tumor spheroid models have been developed to co-culture cancer cells with endothelial cells 52,53 , fibroblasts 53,54 , stellate cells 55 , or various immune cells [56][57][58][59][60] ; and three-way co-cultures are emerging 61,62 . While evidence for the influence of intratumor bacteria on cancer progression builds, this BSCC with colorectal cancer-associated intratumor bacteria adds a novel model to study this disease.…”

New artery of knowledge: 3D models of angiogenesis

“…In VMO, endothelial cells form a luminised, perfusable, vascular network that respond to shear stress (76) EC-coculture spheroids Assessing the interplay between endothelial cells and mural cells and special growth of vascular structures, in physiological and pathological conditions. Drug screening (58,77,78) Ex vivo (organotypic assays)…”