Mechanisms of tumour progression

The progression of primary tumour cells to acquire an invasive phenotype is a critical step in cancer development. Oncogenic mutations and the contribution of signalling pathways that organise cytoskeletal proteins have the ability to equip tumour cells with motility and invasiveness.

The tumour microenvironment, including fibroblasts, endothelial cells and tumour associated immune cells, is a primary source of growth factors, cytokines and chemokines that govern tumour progression.

These secreted proteins provide not only mitogenic signals, but also activate the crucial signalling pathways that lead to immunosuppression, angiogenesis and tumour cell motility. These coordinated molecular events enable tumour cells to invade the surrounding tissues, followed by intravasation and vascular/ lymphatic spread to distant sites of the body where they form metastasis.

Our aim is to find cellular and molecular targets in the events of tumour progression and metastasis.

Tumour associated macrophages
We focus on the inhibition of the recruitment of tumour promoting macrophages to the tumour microenvironment via chemokine signalling. We also aim to decipher the active role of tissue resident macrophages in the regulation of immune responses after tumour challenge.

Targeting melanoma progression
This project utilises potent small molecule inhibitors against novel protein targets in melanoma. Our aim is to find effective anti-cancer drugs for triple negative (BRAF, PTEN, NRAS) metastatic melanoma.

We have shown that the recruitment of tumour associated macrophages to pulmonary metastasis of melanoma involves different CC chemokine receptors responding to chemokines secreted by the tumour cells and the tumour microenvironment. Inhibiting chemokine receptors responsible for the recruitment of the tumour promoting but not the anti-tumour macrophage phenotype can provide a means to suppress tumour growth and progression.

Publications

Tapmeier TT, Gal A, Muschel RJ. The response of infiltrating and resident macrophages to melanoma challenge in the mouse lung: Involvement of the CC-chemokine axis in the recruitment of pro-tumoral macrophages. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; Cancer Res 2013; 73(8 Suppl)

Im JH, Tapmeier TT, Balathasan L, Gal A, Yameen S, Hill S, Smart S, Noterdaeme O, Kelly M, Brady M, Fu W, Kruse K, Bernhard EJ., Augustin HG., Muschel RJ. G-CSF rescues tumour growth and neo-angiogenesis during liver metastasis under host angiopoietin-2 deficiency. Int J Cancer 2013; 132(2):315-3216

Gal A, Tapmeier TT, Muschel RJ: Plasticity of tumour associated macrophages in a metastatic melanoma model in the mouse. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; Cancer Res 2012; 72(8 Suppl)

Muschel RJ, Gal A. Tetraspanin in oncogenic epithelial-mesenchymal transition. J Clin Invest, 2008; 118:1347-50

Gal A, Sjöblom T, Fedorova L, Imreh S, Beug H, Moustakas A: Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene, 2008; 27:1218-30

Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T, Schreiber M, Jechlinger M, Beug H: ILEI: A cytokine essential for EMT, tumour formation, and late events in metastasis in epithelial cells. Cancer Cell, 2006; 10:227-239