Pancreatic Cancer Organotypic Models

Coetzee, Abigail; Grose, Richard; Kocher, Hemant M.

doi:10.1007/82_2019_155

Cited by 5 publications

(8 citation statements)

References 34 publications

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“…1A ). This reduction in invasion was also confirmed in another longer duration, physiomimetic 3D co-culture organotypic model [ 21 ], where cancer cells and PSCs are seeded on top of a Collagen: Matrigel hydrogel and allowed to grow and invade over seven days (Fig. 1C, D ).…”

Section: Resultssupporting

confidence: 65%

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Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1

et al. 2022

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Pancreatic stellate cells (PSCs) are key to the treatment-refractory desmoplastic phenotype of pancreatic ductal adenocarcinoma (PDAC) and have received considerable attention as a stromal target for cancer therapy. This approach demands detailed understanding of their pro- and anti-tumourigenic effects. Interrogating PSC-cancer cell interactions in 3D models, we identified nuclear FGFR1 as critical for PSC-led invasion of cancer cells. ChIP-seq analysis of FGFR1 in PSCs revealed a number of FGFR1 interaction sites within the genome, notably NRG1, which encodes the ERBB ligand Neuregulin. We show that nuclear FGFR1 regulates transcription of NRG1, which in turn acts in autocrine fashion through an ERBB2/4 heterodimer to promote invasion. In support of this, recombinant NRG1 in 3D model systems rescued the loss of invasion incurred by FGFR inhibition. In vivo we demonstrate that, while FGFR inhibition does not affect the growth of pancreatic tumours in mice, local invasion into the pancreas is reduced. Thus, FGFR and NRG1 may present new stromal targets for PDAC therapy.

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Section: Resultssupporting

confidence: 65%

“…Cells were grown in the 3D mini-organotypic model as previously described [ 21 ]. Cells were left for 24 h to attach to the gel before treatments were added into the medium below the Transwell insert.…”

Section: Methodsmentioning

confidence: 99%

Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1

et al. 2022

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“…4A-D). Importantly, in 3D organotypic cocultures, which do not pre-contain hyaluronan 21 , but is deposited by PSC actively, the reduction in PTX3 expression induced by ATRA was also associated with reduced hyaluronan stabilization and invasion (Fig. 4E-H).…”

Section: Introductionmentioning

confidence: 92%

Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

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“…To assess these findings in a controlled model system, an organotypic culture model was used [25,26]. In this model, tumor cells and primary PSCs (PS-1) were co-cultured on a 3D ECM gel with an air-liquid interface, to stimulate stratification of the epithelium (Fig EV1C).…”

Section: High-grade Pdac Features Stroma That Is Low In Collagen and ...mentioning

confidence: 99%

High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.

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Pancreatic Cancer Organotypic Models

Cited by 5 publications

References 34 publications

Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1

Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1

Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1

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