Abstract
Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor β availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma.
| Original language | English |
|---|---|
| Pages (from-to) | 90-104 |
| Number of pages | 15 |
| Journal | The Journal of Pathology |
| Volume | 262 |
| Issue number | 1 |
| Early online date | 6 Nov 2023 |
| DOIs | |
| Publication status | Published - 31 Jan 2024 |
Bibliographical note
Funding Information:We thank the CMR Advanced Bio‐Imaging Facility at QMUL and Microscopy Core Facility at BCI for the use, help, and advice with microscopy. We thank Luke Gammon and the QMUL Phenotypic Screening Facility for help with high content imaging. We thank Chaz Mein and the Genomics Core at QMUL for assistance with RNA sequencing. We thank Vinothini Rajeeve and the Mass Spectrometry Core Facility at BCI for help with proteomics. EC was funded by CRUK (A27781), KY was supported by a Barts Charity Grant (G‐002189). This work was also funded by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137).
Funding
We thank the CMR Advanced Bio‐Imaging Facility at QMUL and Microscopy Core Facility at BCI for the use, help, and advice with microscopy. We thank Luke Gammon and the QMUL Phenotypic Screening Facility for help with high content imaging. We thank Chaz Mein and the Genomics Core at QMUL for assistance with RNA sequencing. We thank Vinothini Rajeeve and the Mass Spectrometry Core Facility at BCI for help with proteomics. EC was funded by CRUK (A27781), KY was supported by a Barts Charity Grant (G‐002189). This work was also funded by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137). We thank the CMR Advanced Bio-Imaging Facility at QMUL and Microscopy Core Facility at BCI for the use, help, and advice with microscopy. We thank Luke Gammon and the QMUL Phenotypic Screening Facility for help with high content imaging. We thank Chaz Mein and the Genomics Core at QMUL for assistance with RNA sequencing. We thank Vinothini Rajeeve and the Mass Spectrometry Core Facility at BCI for help with proteomics. EC was funded by CRUK (A27781), KY was supported by a Barts Charity Grant (G-002189). This work was also funded by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137).
| Funders | Funder number |
|---|---|
| Cancer Research UK Centre | |
| Mass Spectrometry Core Facility | |
| Cancer Research UK | G‐002189, A27781 |
| Barts Cancer Institute | A25137 |
Keywords
- 3D in vitro models
- TGFβ
- cancer invasion
- cancer-associated fibroblasts
- cellular cross talk
- extracellular matrix
- myofibroblast
- pancreatic cancer
- protease
ASJC Scopus subject areas
- Pathology and Forensic Medicine
