Cancer Progression Upon Loss of Cell Adhesion
Focus:
Breast cancer is the most common malignancy among females in the Western world resulting in approximately half a million deaths on an annual basis. In breast cancer, loss of E-cadherin is a decisive marker in the differential diagnosis of lobular and ductal carcinoma. While lobular carcinomas show loss of E-cadherin, most other breast carcinomas have retained expression. E-cadherin is a key component of adherens junctions, structures that play crucial roles in the maintenance of tissue integrity. Dysfunction of epithelial adhesion complexes is strongly related to cancer invasion and metastasis.
We are using mouse and human models of breast cancer in which inactivation of cell-cell adhesion through disruption of the adherens junction complex induces the formation of metastatic breast cancer. We are using several cell lines from our mouse models and human breast cancer to form a cell biological basis for understanding the malignant behaviour of invasive cancer. We aim to identify the molecular cues that are triggered upon loss of cadherin-based cell-cell adhesions. For validation purposes, we have developed robust in vivo tumor progression and metastasis assays, based on orthotopic transplantation and bioluminescence imaging of luciferase-expressing cell lines, tumors and primary conditional and wild-type mouse mammary epithelial cells. We are using these assays to validate genes that are nominated as novel regulators of tumor initiation and progression. To translate our findings, we are preforming preclinical interventions in mouse models of human metastatic breast cancer, with the ultimate goal to implement new interventions to improve cancer treatment.
Breast cancer is the most common malignancy among females in the Western world resulting in approximately half a million deaths on an annual basis. In breast cancer, loss of E-cadherin is a decisive marker in the differential diagnosis of lobular and ductal carcinoma. While lobular carcinomas show loss of E-cadherin, most other breast carcinomas have retained expression. E-cadherin is a key component of adherens junctions, structures that play crucial roles in the maintenance of tissue integrity. Dysfunction of epithelial adhesion complexes is strongly related to cancer invasion and metastasis.
We are using mouse and human models of breast cancer in which inactivation of cell-cell adhesion through disruption of the adherens junction complex induces the formation of metastatic breast cancer. We are using several cell lines from our mouse models and human breast cancer to form a cell biological basis for understanding the malignant behaviour of invasive cancer. We aim to identify the molecular cues that are triggered upon loss of cadherin-based cell-cell adhesions. For validation purposes, we have developed robust in vivo tumor progression and metastasis assays, based on orthotopic transplantation and bioluminescence imaging of luciferase-expressing cell lines, tumors and primary conditional and wild-type mouse mammary epithelial cells. We are using these assays to validate genes that are nominated as novel regulators of tumor initiation and progression. To translate our findings, we are preforming preclinical interventions in mouse models of human metastatic breast cancer, with the ultimate goal to implement new interventions to improve cancer treatment.
