Publication
Bioengineered pancreatic tumor-stroma models for preclinical screening of therapeutics
| Summary: | Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging diseases to treat with a very poor prognosis, exhibiting a 5-year survival rate of less than 10%. This dismal scenario arises from the late detection, rapid progression, and inefficacy of currently available treatments. Its aggressiveness and resistance are largely attributed to the dense fibrotic stroma and poor vascularization, hampering anti-cancer drugs delivery to malignant cells. In an attempt to accelerate the discovery and validation of new and more effective therapies, research has been focused on the development of increasingly biomimetic and predictive preclinical tumor models for the identification of new therapeutic targets and the screening of novel treatment approaches. Despite the efforts, most preclinical platforms still fail on resembling native tumor microenvironment (TME) of this neoplasia, especially the unique tumor-stroma organization and its complex biological interplay. A number of three-dimensional (3D) models have been fabricated aiming to recreate human TME namely, spheroids, hydrogel-based systems, cancer-on-a-chip, and 3D bioprinted constructs. Despite representing human tumors closer than the monolayer cultures, they generally still lack any prior representation of stroma components in a relevant manner. Therefore, this PhD thesis focuses on the bioengineering of advanced pancreatic cancer models, capable of more faithfully emulating the unique tumor-stroma interactions and architecture, where the core tumor mass is enveloped by a dense and fibrotic stroma compartment. A comprehensive overview of pancreatic TME and 3D in vitro tumor modeling is provided for contextualization of the current state-of-the-art of the field. Advances in cutting edge technologies such as 3D bioprinting and cryobioprinting to produce more complex human-scale 3D in vitro platforms are also highlighted. The bioengineering of tumor-stroma core-shell pancreatic cancer models by using scaffold-free and scaffold-based methods is focused with the aim to demonstrate the ability to produce tumor-stroma models, where the tumor core is encapsulated by a stroma compartment, and the crucial recapitulation of this hallmark on anti-cancer drugs response. Such core-shell structures were generated by using either ultra-low adhesion plates or superhydrophobic surfaces. The establishment of tumor-stroma models by using tissue-specific decellularized extracellular matrix (dECM) is herein also reported aiming to generate pancreas dECM-based miniaturized tumor-stroma platforms in a high-throughput manner and demonstrating the impact of PDAC stroma in chemoresistance. The screening of stroma-targeted therapies in combination with anti-cancer therapies was conducted and enabled the validation of the established tumor-stroma model potential for screening stroma ablation approaches to improve current treatments efficacy. The development of more complex and tissue-scale models for preclinical drug screening was performed through 3D bioprinting technology and the ability to produce and cryopreserve such platforms simultaneously during fabrication was carried out by employing 3D cryobioprinting technologies. 3D cryobioprinted and preserved tumor-stroma PDAC models showed potential to be used on-demand as off-the-shelf available platforms, emerging as an innovative alternative for preclinical drug-screening. Overall, the developed preclinical testing platforms level-up the current landscape of PDAC in vitro models being useful for unveiling innovative treatments for this disease and to potentially assist in bedside clinical decision making in the foreseeable future. |
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| Main Authors: | Monteiro, Maria Vinhas |
| Subject: | Pancreatic cancer Extracellular matrix mimetic hydrogels 3D in vitro tumor models 3D bioprinting Drug screening |
| Year: | 2025 |
| Country: | Portugal |
| Document type: | doctoral thesis |
| Access type: | embargoed access |
| Associated institution: | Universidade de Aveiro |
| Language: | English |
| Origin: | RIA - Repositório Institucional da Universidade de Aveiro |
| Summary: | Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging diseases to treat with a very poor prognosis, exhibiting a 5-year survival rate of less than 10%. This dismal scenario arises from the late detection, rapid progression, and inefficacy of currently available treatments. Its aggressiveness and resistance are largely attributed to the dense fibrotic stroma and poor vascularization, hampering anti-cancer drugs delivery to malignant cells. In an attempt to accelerate the discovery and validation of new and more effective therapies, research has been focused on the development of increasingly biomimetic and predictive preclinical tumor models for the identification of new therapeutic targets and the screening of novel treatment approaches. Despite the efforts, most preclinical platforms still fail on resembling native tumor microenvironment (TME) of this neoplasia, especially the unique tumor-stroma organization and its complex biological interplay. A number of three-dimensional (3D) models have been fabricated aiming to recreate human TME namely, spheroids, hydrogel-based systems, cancer-on-a-chip, and 3D bioprinted constructs. Despite representing human tumors closer than the monolayer cultures, they generally still lack any prior representation of stroma components in a relevant manner. Therefore, this PhD thesis focuses on the bioengineering of advanced pancreatic cancer models, capable of more faithfully emulating the unique tumor-stroma interactions and architecture, where the core tumor mass is enveloped by a dense and fibrotic stroma compartment. A comprehensive overview of pancreatic TME and 3D in vitro tumor modeling is provided for contextualization of the current state-of-the-art of the field. Advances in cutting edge technologies such as 3D bioprinting and cryobioprinting to produce more complex human-scale 3D in vitro platforms are also highlighted. The bioengineering of tumor-stroma core-shell pancreatic cancer models by using scaffold-free and scaffold-based methods is focused with the aim to demonstrate the ability to produce tumor-stroma models, where the tumor core is encapsulated by a stroma compartment, and the crucial recapitulation of this hallmark on anti-cancer drugs response. Such core-shell structures were generated by using either ultra-low adhesion plates or superhydrophobic surfaces. The establishment of tumor-stroma models by using tissue-specific decellularized extracellular matrix (dECM) is herein also reported aiming to generate pancreas dECM-based miniaturized tumor-stroma platforms in a high-throughput manner and demonstrating the impact of PDAC stroma in chemoresistance. The screening of stroma-targeted therapies in combination with anti-cancer therapies was conducted and enabled the validation of the established tumor-stroma model potential for screening stroma ablation approaches to improve current treatments efficacy. The development of more complex and tissue-scale models for preclinical drug screening was performed through 3D bioprinting technology and the ability to produce and cryopreserve such platforms simultaneously during fabrication was carried out by employing 3D cryobioprinting technologies. 3D cryobioprinted and preserved tumor-stroma PDAC models showed potential to be used on-demand as off-the-shelf available platforms, emerging as an innovative alternative for preclinical drug-screening. Overall, the developed preclinical testing platforms level-up the current landscape of PDAC in vitro models being useful for unveiling innovative treatments for this disease and to potentially assist in bedside clinical decision making in the foreseeable future. |
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