The Brodt laboratory is studying the biology and clinical aspects of cancer metastasis with emphasis on the process of liver metastasis. Within this context, the following specific projects are being pursued:
1) The role of the IGF axis in liver metastasis: signaling and crosstalk with the microenvironment
In this project, we investigate the role of the IGF axis in regulating the malignant phenotype of different tumor cell types, in particular the role it plays in tumor cell invasion, the production of metalloproteinases, angiogenesis, lymphangiogenesis and resistance to apoptosis. To this end, we utilize a combination of gene-altered mouse models and genetically modified cancer cells.
Recent representative publication: Burnier,J.V., Wang,N., Michel,R.P., Hassanain,M., Li S., Lu, Y., Metrakos,P., Antecka, E., Burnier,M.N., Ponton,A., Gallinger, S. and BrodtP. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene 30:3766-83, 2011.
Source: Burnier, J.V. et al. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene 30:3766-83, 2011.
2) The pro-metastatic microenvironment of the liver: role of inflammation
In this project, we aim to dissect the crosstalk between cancer cells entering the liver and different cellular/molecular elements of the liver microenvironment. To this end, we are studying mice with genetically modified inflammatory responses such as TNF receptor deficiencies to dissect the role of different immune cell subsets in the process of metastasis.
Recent representative publication: Li, S., Wang, N. and Brodt, P. Metastatic cells can escape the pro-apoptotic effects of an inflammatory microenvironment by utilizing TNF-alpha to increase IL-6 production and signalling- Cancer Research, 72: 865-875, 2012.
Source: Brodt, P. Surviving host innate immunity: Cancer cells can turn a deadly assault
into an advantage. OncoImmunology 1(9): 1601–1603, 2012.
3) Developing an IGF Trap for prevention of cancer growth and metastasis
The objective of this project is to develop novel strategies for targeting the IGF axis as means of blocking cancer growth and metastasis. To this end, we have used cell and gene therapy strategies for delivering a soluble IGF-receptor in vivo into tumor-bearing mice and observed significant cancer growth inhibition. Presently a soluble IGF-TRAP is being developed as an anti-cancer drug.
Recent representative publication: Wang, N., Lu, Y., Pilotte, A.,Yu, Z., Gilbert,R., Massie, B. and Brodt, P. Adenovirus particles engineered to express a soluble IGF-I receptor can induce production of therapeutically relevant plasma protein levels and protect from liver metastasis. Cancer Gene Therapy, 20 (4): 229-36, 2013.
Source: Wang, N.et al. Autologous bone marrow derived mesenchymal stromal cells genetically engineered to express
an IGF-I receptor decoy prevent the growth of liver metastases. Mol. Ther, 17:1241-9, 2009.