Translating complexity and heterogeneity of pancreatic tumor: 3D in vitro to in vivo models

Heinrich, Marcel A.; Mostafa, Ahmed M.R.H.; Morton, Jennifer P.; Hawinkels, Lukas J.A.C.; Prakash, Jai

doi:10.1016/j.addr.2021.04.018

Cited by 71 publications

(60 citation statements)

References 340 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, 3D organoid cultures of primary cell lines derived from a variety of organs have been developed ( Barker et al, 2010 ) ( Sato et al, 2011 ) ( Huch et al, 2015 ) ( Rosenbluth et al, 2020 ), including those of the pancreatic ductal epithelium and their tumor counterparts ( Boj et al, 2015 ) ( Baker et al, 2016 ). A contemporary review comprehensively explores developments of PDAC culture models for broad application ( Heinrich et al, 2021 ), however, typically PDAC organoid cultures are maintained in a 3D hydrogel-based scaffold comprised of a variety of basement membrane proteins such as Matrigel ( Baker et al, 2016 ). Matrigel is derived from basement membrane extracts of murine Engelbreth-Holm-Swarm sarcoma, and contains laminin, collagen type IV, and entactin ( Kleinman and Martin, 2005 ).…”

Section: Models To Study Interactions With Extracellular Matrix and Tension/pressurementioning

confidence: 99%

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

Maneshi

Mason

Dongre

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

show abstract

Section: Models To Study Interactions With Extracellular Matrix and Tension/pressurementioning

confidence: 99%

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

Maneshi

Mason

Dongre

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In order to better understand cell-stromal interactions and make accurate treatment predictions, 3D models offer a better alternative compared to 2D systems as they more closely recapitulate processes such as cell-cell, cell-matrix interaction, tumor heterogeneity and gradient formation of nutrients, oxygen, and drugs (Table 1). When compared to mouse models, 3D models are considerably more accessible and amenable to genetic manipulation (Heinrich et al, 2021). Here we describe different 3D models developed that have application in immune oncology.…”

Section: D Models To Investigate Immuno-oncology In Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

PDAC as an Immune Evasive Disease: Can 3D Model Systems Aid to Tackle This Clinical Problem?

Narayanan

Vicent

Ponz-Sarvisé

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, “hot” tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.

show abstract

“…[21][22][23] Considering the importance of such unique tumor-stroma niche in the resistance to therapeutics, evermore evolved 3D in vitro models are currently under development for recapitulating PDAC unique bioarchitecture and active stroma in an attempt to bioengineer more physiomimetic models. [24] Recently, we generated heterotypic 3D PDAC stratified microenvironment spheroid models-so termed STAMS-comprising pancreatic cancer cells and CAFs organized in a stratified mode aiming to reproduce PDAC niche key signatures. [5] These platforms were highly robust in mirroring the desmoplastic reaction, stratified architecture and drug resistance in a controlled laboratory setting.…”

Section: Introductionmentioning

confidence: 99%

Programmable Living Units for Emulating Pancreatic Tumor‐Stroma Interplay

Monteiro

Rocha

Gaspar

et al. 2022

Adv Healthcare Materials

View full text Add to dashboard Cite

Bioengineering close-to-native in vitro models that emulate tumors bioarchitecture and microenvironment is highly appreciable for improving disease modeling toolboxes. Herein, pancreatic cancer living units-so termed cancer-on-a-bead models-are generated. Such user-programmable in vitro platforms exhibit biomimetic multicompartmentalization and tunable integration of cancer associated stromal elements. These stratified units can be rapidly assembled in-air, exhibit reproducible morphological features, tunable size, and recapitulate spatially resolved tumor-stroma extracellular matrix (ECM) niches. Compartmentalization of pancreatic cancer and stromal cells in well-defined ECM microenvironments stimulates the secretion of key biomolecular effectors including transforming growth factor 𝜷 and Interleukin 1-𝜷, closely emulating the signatures of human pancreatic tumors. Cancer-on-a-bead models also display increased drug resistance to chemotherapeutics when compared to their reductionistic counterparts, reinforcing the importance to differentially model ECM components inclusion and their spatial stratification as observed in vivo. Beyond providing a universal technology that enables spatial modularity in tumor-stroma elements bioengineering, a scalable, in-air fabrication of ECM-tunable 3D platforms that can be leveraged for recapitulating differential matrix composition occurring in other human neoplasias is provided here.

show abstract

Translating complexity and heterogeneity of pancreatic tumor: 3D in vitro to in vivo models

Cited by 71 publications

References 340 publications

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

PDAC as an Immune Evasive Disease: Can 3D Model Systems Aid to Tackle This Clinical Problem?

Programmable Living Units for Emulating Pancreatic Tumor‐Stroma Interplay

Contact Info

Product

Resources

About