Biology subjects

Marshall, J. F.

Publications and source records attributed to Marshall, J. F..

4 recordsLinked to original sources

bioRxiv2025

Ephrin inhibition disrupts stromal-cancer crosstalk and reduces metastasis in pancreatic cancer

Cancer associated fibroblasts (CAFs) are critical drivers of disease progression and metastasis within the pancreatic tumour microenvironment. Using a 3D spheroid model of CAF-led invasion, we identified complementary expression of ephrin family receptors (EPHB2) and ligands (EPHRINB2) between cancer cells and CAFs, implicating this bidirectional signalling family in tumour progression. Through pancreatic stellate cell-derived CAFs isolated from genetically modified mouse models, where EphrinB was either lacking or modified by a gain-of-function mutation, we identified both forward and reverse signalling to be required for invasion. In a syngeneic murine orthotopic model of pancreatic cancer, we show that first-in-class tetramerisation inhibitors of Eph/Ephrin interactions can reduce local invasion in primary tumours, and significantly decrease metastatic tumour spread across multiple organ sites. Our data highlight Ephrin signalling as a critical nexus for CAF-cancer crosstalk and establish a foundation for the clinical development of targeted EPH-EPHRIN inhibitors to counter metastatic invasion.

cancer biology↗

bioRxiv2025

Pancreatic cancer metastasis is regulated by an eleven amino-acid sequence

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis with a 5-year survival rate less than 5% because of its ability to metastasise, its late detection and the lack of effective therapies. The Integrin v{beta}6 is highly overexpressed in PDAC and correlates with poor prognosis. The integrin {beta}6 subunit contains a unique C-terminal tail of 11 amino acids (aa) that regulates downstream signals, although the mechanism remains unclear. Here, using integrin {beta}6-deficient cells lines, we have developed two PDAC mouse models overexpressing the full-length {beta}6 and a mutant {beta}6 lacking the C-terminal 11aa (v{Delta}{beta}6). In vitro, v{beta}6 overexpression increased cell proliferation, migration and invasion in a 3D spheroid model. The elimination of the C-terminal 11aa decreased proliferation and totally impaired cell migration and invasion. v{Delta}{beta}6 cells also expressed reduced MMPs in vitro. In vivo, orthotopic implantation of v{beta}6 overexpressing cells showed decreased overall survival and more spontaneous metastasis compared to v{Delta}{beta}6 and v{beta}6-null cells. Therefore, the C-terminal 11aa of the integrin {beta}6 subunit regulates PDAC progression and metastasis.

cancer biology↗

bioRxiv2025

Matrix structure and microenvironment dynamics correlate with chemotherapy response in ovarian cancer

Elevated extracellular matrix (ECM) in the tumor microenvironment (TME) is associated with chemoresistance and poor prognosis. We hypothesized that modifying the ECM may enhance response to chemotherapy. We measured chemotherapy-induced changes in the TME of two mouse models of high-grade serous ovarian cancer (HGSOC) that differed in chemotherapy response. Treatment of the chemo-sensitive tumors triggered dynamic transcriptional ECM and immune changes and structural modifications of ECM proteins. These changes, observed over twenty-days post-chemotherapy, had relevance to HGSOC patient responses to chemotherapy. Integrating transcriptomics with ECM structure metrics, we identified ECM targets, including lysyl oxidase (LOX), that might enhance chemotherapy in less responsive mouse tumors. Given alone or in combination with chemotherapy, a pan-LOX inhibitor (PXS-5505) modulated fibroblast and immune cell distribution and reduced tumor stiffness in HGSOC chemo-resistant mouse tumors. Moreover, pre-treatment with PXS-5505 improved response to chemotherapy. We conclude that pretreatment with ECM targeting agents may improve response to chemotherapy, by altering ECM structure and immune responses.

cancer biology↗

bioRxiv2018

Integrin αVβ6-EGFR crosstalk regulates bidirectional force transmission and controls breast cancer invasion

The mechanical properties of the extracellular matrix within tumours control multiple cellular functions that drive cancer invasion and metastasis. However, the mechanisms controlling microenvironmental force sensation and transmission, and how these regulate transcriptional reprogramming and invasion, are unclear. Our aim was to understand how mechanical inputs are transmitted bidirectionally and translated into biochemical and transcriptional outputs to drive breast cancer progression. We reveal that adhesion receptor and growth factor receptor crosstalk regulates a bidirectional feedback mechanism co-ordinating force-dependent transcriptional regulation and invasion.\n\nIntegrin V{beta}6 drives invasion in a range of carcinomas and is a potential therapeutic target. V{beta}6 exhibits unique biophysical properties that promote force-generation and increase matrix rigidity. We employed an inter-disciplinary approach incorporating proteomics, biophysical techniques and multi-modal live-cell imaging to dissect the role of V{beta}6-EGFR crosstalk on transmission of mechanical signals bidirectionally between the extracellular matrix and nucleus.\n\nWe show that V{beta}6 expression correlates with poor prognosis in triple-negative breast cancer (TNBC) and drives invasion of TNBC cells. Moreover, our data show that a complex regulatory mechanism exists involving crosstalk between V{beta}6 integrin and EGFR that impacts matrix stiffness, force transmission to the nucleus, transcriptional reprogramming and microenvironment rigidity. V{beta}6 engagement triggers EGFR & MAPK signalling and V{beta}6-EGFR crosstalk regulates mutual receptor trafficking mechanisms. Consequently, EGF stimulation suppresses V{beta}6-mediated force-application on the matrix and nuclear shuttling of force-dependent transcriptional co-activators YAP/TAZ. Finally, we show that crosstalk between V{beta}6 & EGFR regulates TNBC invasion.\n\nWe propose a model whereby V{beta}6-EGFR crosstalk regulates matrix stiffening, but also the transmission of extracellular forces into the cell in order to co-ordinate transcriptional reprogramming and invasion. To exploit adhesion receptors and receptor tyrosine kinases therapeutically, it will be essential to understand the integration of their signalling functions and how crosstalk mechanisms influence invasion and the response of tumours to molecular therapeutics.

cancer biology↗