PDAC-on-chip for <i>in vitro</i> modeling of stromal and pancreatic cancer cell crosstalk

Sgarminato, Viola; Cocuzza, Matteo; Scordo, Giorgio; Ballesio, Alberto; Ciardelli, Gianluca; Tonda‐Turo, Chiara

doi:10.1039/d2bm00881e

Cited by 10 publications

(8 citation statements)

References 95 publications

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“…After injection, the constructs were placed in 24-well plates, with enough cell medium to keep them hydrated, but not enough to cover the entry of the lumen, to prevent HPDE cells from floating into the media. Co-cultures were maintained in DMEM/F-12 supplemented with 15% FBS (Gibco), 1% Penicillin-Streptomycin (Gibco) and 2% L-glutamine (Gibco) since previous tests demonstrated the efficacy of this culture medium composition in promoting the cell viability 86 . Two hours later, more medium was added to the wells, this time covering the full constructs.…”

Section: Methodsmentioning

confidence: 99%

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3Din vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting

Sgarminato

Madrid‐Wolff

Boniface

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer, one of the leading causes of cancer-related deaths worldwide. PDAC is marked by a dense, fibrous tumor microenvironment, in which stromal fibroblasts surround the cancerous ductal epithelial cells. The crosstalk between pancreatic cells and the surrounding fibroblasts leads to inflammation and stiffening of the surrounding tissue, which is believed to hinder anti-cancer drugs' uptake and effectiveness. In vitro, fully human models of the pancreatic cancer microenvironment are needed to foster the development of new, more effective therapies; but it is still challenging to make these models anatomically and functionally relevant. Here, we use tomographic volumetric bioprinting, a novel method to fabricate cell-laden viable constructs within less than a minute, to produce anatomically relevant fibroblast-laden gelatine methacrylate-based pancreatic models, including a duct and an acinus. We then seeded human pancreatic ductal epithelial (HPDE) cells, wild type or cancerous, into these models and evaluated the progression of the constructs for several days after printing. We show that the 3D pancreatic duct models remain viable for up to 14 days after bioprinting. We used immunofluorescence to evaluate the surrounding fibroblasts' activation by quantifying the relative expressions of alpha smooth muscle actin (αSMA) vs. actin in the fibroblasts. αSMA is known to be overexpressed in inflamed tumor-associated fibroblasts. We show that αSMA expression is significantly higher in fibroblasts co-cultured with cancerous than with wild-type HPDE cells, that this expression increases with time, and that it is higher in fibroblasts that lay closer to HPDE cells than in those deeper into the model. These models could potentially be used in drug development or to shed light on the early progression of the disease.

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Section: Methodsmentioning

confidence: 99%

“…Co-cultures were maintained in DMEM/F-12 supplemented with 15% FBS (Gibco), 1% Penicillin-Streptomycin (Gibco) and 2% L-glutamine (Gibco) since previous tests demonstrated the efficacy of this culture medium composition in promoting the cell viability 103 . the constructs were kept in a humidified CO 2 incubator at 37 °C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

3Din vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting

Sgarminato

Madrid‐Wolff

Boniface

et al. 2023

Preprint

Self Cite

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“…We further assessed the a-SMA expression, which is a common biomarker of CAFs, 51,52 in the desmoplastic PDAC spheroids to explore whether normal fibroblasts were activated and obtained the CAF phenotype during co-culturing. Fig.…”

Section: Bioprinting Of Pdac Tumor Spheroidsmentioning

confidence: 99%

Embedded bioprinted multicellular spheroids modeling pancreatic cancer bioarchitecture towards advanced drug therapy

Wei,

Wu,

Chen

et al. 2024

J. Mater. Chem. B

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“…Another study employed a multilayer PDAC-on-chip design to culture PDAC cells, PSCs, and fibroblasts in separate compartments. The findings revealed that fibroblasts altered their morphology to a myofibroblast-like shape and secreted increased amounts of IL-6 in the presence of cancer cells, potentially modeling the early steps of PDAC evolution ( Sgarminato et al, 2023 ). The incorporation of vascularization into tumor-chips is a crucial strategy to mimic proper in vivo physiology, particularly for PDAC where high interstitial pressure leads areas of vascular collapse and poor perfusion.…”

Section: Current Microphysiological Systems Of ‘Cold’ Tumorsmentioning

confidence: 99%

Microphysiological systems as models for immunologically ‘cold’ tumors

Gaebler,

Hachey,

Hughes

2024

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically ‘cold’ tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in ‘cold’ tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various ‘cold’ tumors. Understanding the intricacies of the TME in ‘cold’ tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

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PDAC-on-chip for in vitro modeling of stromal and pancreatic cancer cell crosstalk

Abstract: Pancreatic ductal adenocarcinoma (PDAC) mainly develops in the head of the pancreas, within the acino-ductal unit composed by acinar and ductal cells surrounded by pancreatic stellate cells (PSCs). PSCs strongly...

Cited by 10 publications

References 95 publications

3Din vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting

3Din vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting

Embedded bioprinted multicellular spheroids modeling pancreatic cancer bioarchitecture towards advanced drug therapy

Microphysiological systems as models for immunologically ‘cold’ tumors

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