Final Report Summary - PTPSMETBC (Roles of SHP2 and other protein tyrosine phosphatases in metastatic breast cancer)
During my post-doctoral studies in the laboratory of Dr. Mohamed Bentires-Alj, financed by the FP7 Marie Curie fellowship, I achieved new knowledge in metastatic breast cancer, in the tumor microenvironment and in multiphoton-intravital imaging. My work led to the publication of two articles in peer reviewed journals.
Each year, breast cancer is diagnosed in ~1.5 million women worldwide and ~500,000 lives are lost to this disease. Patients may do well after surgery and initial treatment, but drug resistance and fatal metastases often develop. The majority of deaths related to breast cancer are due to metastasis, the spread and growth of cancer cells in distant organs. Curing metastatic breast cancer clearly represents an unmet medical need and improved treatment options are urgently needed. To develop new therapies, a deep understanding of the mechanisms triggering metastasis is needed, from the invasion of the cells at the primary site of the breast to the colonization of the metastatic niche in the distant organs like the lungs.
The article “Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases” has been published in Oncogene (Sausgruber*, Coissieux* et al, 2015). In this publication, we have identified a crucial effect of SHP2 on triple negative breast cancer cell motility in vivo using multiphoton-intravital imaging. SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay (FRET). These results suggest that SHP2 is a crucial factor during early steps of triple negative breast cancer migration to distant organs. Targeting SHP2 in patients may prevent cancer cell escape from the primary tumor to form metastasis.
The article “Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis” has been published in Nature (Bonapace*, Coissieux* et al, 2014). It has been shown that secretion of C–C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. We have reported a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Anti-CCL2 treatment decreased lung metastases, but surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin IL-6- and vascular endothelial growth factor VEGF-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals.
Each year, breast cancer is diagnosed in ~1.5 million women worldwide and ~500,000 lives are lost to this disease. Patients may do well after surgery and initial treatment, but drug resistance and fatal metastases often develop. The majority of deaths related to breast cancer are due to metastasis, the spread and growth of cancer cells in distant organs. Curing metastatic breast cancer clearly represents an unmet medical need and improved treatment options are urgently needed. To develop new therapies, a deep understanding of the mechanisms triggering metastasis is needed, from the invasion of the cells at the primary site of the breast to the colonization of the metastatic niche in the distant organs like the lungs.
The article “Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases” has been published in Oncogene (Sausgruber*, Coissieux* et al, 2015). In this publication, we have identified a crucial effect of SHP2 on triple negative breast cancer cell motility in vivo using multiphoton-intravital imaging. SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay (FRET). These results suggest that SHP2 is a crucial factor during early steps of triple negative breast cancer migration to distant organs. Targeting SHP2 in patients may prevent cancer cell escape from the primary tumor to form metastasis.
The article “Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis” has been published in Nature (Bonapace*, Coissieux* et al, 2014). It has been shown that secretion of C–C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. We have reported a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Anti-CCL2 treatment decreased lung metastases, but surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin IL-6- and vascular endothelial growth factor VEGF-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals.