Abstract
The majority of cancer-related deaths are due to metastatic disease. Despite advances in identifying major drivers of primary tumour growth and the development of novel targeted therapies, there remains an unmet need to develop treatment strategies targeting metastatic disease. It is now well established that successful tumour progression involves a close crosstalk between tumour cells and the microenvironment.
By combining in silico analysis, in vitro 3D (co-)culture assays and in vivo spontaneous and experimental breast cancer metastasis models we show that inhibition of the stromal collagen receptor Endo180 reduces breast cancer metastasis formation.
Analyses of fibroblast gene signatures show a significant correlation of the collagen receptor Endo180 and fibroblast activation in human breast cancer data sets. Knock-down of Endo180 in normal and activated fibroblasts reduced their contractility on soft and stiff hydrogels. Interestingly these findings were independent of collagen. Endo180 knockdown fibroblasts lost the ability to modulate and contract collagen plugs and were less invasive. Furthermore, knock-down made the fibroblasts more fragile and sensitive towards stressful conditions, such as reduced serum and anchorage independent growth. In 3D co-culture spheroids assays wildtype fibroblasts enhanced tumour spheroid growth in contrast to Endo180 knock-down ones. Dissociation of these spheroids showed a reduced number of fibroblasts in Endo180 knock-down co-culture spheres.
To assess the role of stromal Endo180 in vivo, mouse mammary carcinoma cells were orthotopically inoculated into BALB/c wildtype and knockout animals. Mice lacking the stromal collagen receptor had a significant reduction in primary tumour growth and spontaneous metastasis to the lungs. Experimental metastasis assays confirmed these findings. In correlation with our in vitro spheroid results, reduced fibroblasts infiltration was detected in primary tumours of Endo180 knock-out animals compared to wildtype animals.
These data provide evidence that stromal Endo180 plays an essential role in efficient breast cancer metastasis establishment.
By combining in silico analysis, in vitro 3D (co-)culture assays and in vivo spontaneous and experimental breast cancer metastasis models we show that inhibition of the stromal collagen receptor Endo180 reduces breast cancer metastasis formation.
Analyses of fibroblast gene signatures show a significant correlation of the collagen receptor Endo180 and fibroblast activation in human breast cancer data sets. Knock-down of Endo180 in normal and activated fibroblasts reduced their contractility on soft and stiff hydrogels. Interestingly these findings were independent of collagen. Endo180 knockdown fibroblasts lost the ability to modulate and contract collagen plugs and were less invasive. Furthermore, knock-down made the fibroblasts more fragile and sensitive towards stressful conditions, such as reduced serum and anchorage independent growth. In 3D co-culture spheroids assays wildtype fibroblasts enhanced tumour spheroid growth in contrast to Endo180 knock-down ones. Dissociation of these spheroids showed a reduced number of fibroblasts in Endo180 knock-down co-culture spheres.
To assess the role of stromal Endo180 in vivo, mouse mammary carcinoma cells were orthotopically inoculated into BALB/c wildtype and knockout animals. Mice lacking the stromal collagen receptor had a significant reduction in primary tumour growth and spontaneous metastasis to the lungs. Experimental metastasis assays confirmed these findings. In correlation with our in vitro spheroid results, reduced fibroblasts infiltration was detected in primary tumours of Endo180 knock-out animals compared to wildtype animals.
These data provide evidence that stromal Endo180 plays an essential role in efficient breast cancer metastasis establishment.
| Original language | English |
|---|---|
| Publication status | Published - 3 Jul 2019 |
| Event | British Association of Cancer Research Conference : Tumour Microenvironment - Nottingham, UK United Kingdom Duration: 1 Jul 2019 → 3 Jul 2019 |
Conference
| Conference | British Association of Cancer Research Conference |
|---|---|
| Country/Territory | UK United Kingdom |
| City | Nottingham |
| Period | 1/07/19 → 3/07/19 |
