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Dr. Peter Siegel

Research

Dr. Siegel’s research program focuses on elucidating the mechanisms that promote breast cancer metastasis, which represents the most deadly aspect of this disease. Currently, metastatic breast cancer is largely an incurable disease. Our knowledge of the molecular determinants that govern breast cancer metastasis is limited and represents an important and intensive area of investigation to better understand this process.

Metastatic tumor cells must overcome numerous barriers that prevent their dissemination to distant organs and tissues. Traditionally, these steps have been broken down to include local invasion through the basement membrane surrounding the primary lesion, migration and intravasation into the lymphatic or hematogenous systems, survival during transit in the circulation, evasion of host anti-tumor immunity, adhesion/extravasation at the target site and reestablishment of a growing tumor mass in a foreign microenvironment. While these basic requirements must be fulfilled by any metastatic tumor cell, it has long been appreciated that certain types of cancer preferentially metastasize to specific organs and tissues. Indeed, breast cancer cells are known to frequently spread to regional lymph nodes, bone, lung, liver and brain. Several factors are likely to contribute to organ preference during breast cancer metastasis, including the pattern of blood flow leaving the primary tumor, physical entrapment of tumors cells in capillary beds within the metastatic site, tumor/endothelial cell interactions and the ability of tumor cells to productively influence and respond to the metastatic microenvironment. Communication between the tumor and its microenvironment is likely to be the single most important determinant for organ-specific metastasis. Thus, both tumor intrinsic and microenvironmental factors play important roles in controlling breast cancer cells metastasis.

To study the metastatic process, Dr. Siegel’s team has taken two complementary approaches:

1)    Selection of breast cancer populations that are aggressively metastatic to distinct organs, such as the bone, lung and liver. This is done by injecting breast cancer cells into mice, allowing metastases to form (in the bone, lung or liver) and isolating the cells back into culture. They then compare the global gene expression profiles of these aggressive populations with profiles derived from weakly metastatic populations derived from the same parental population of breast cancer cells. In this way, they can identify genes and their encoded proteins whose expression is associated with the metastatic phenotype. They subsequently determine if these candidate genes and gene products are expressed in human primary breast cancer samples and metastases. Those whose expression is associated with human breast cancer are prioritized for functional studies using their cell-based and animal models.

2)    Laser capture microdissection on bone and liver metastases derived from patients with breast cancer. In this way, they generate a gene expression profile in breast cancer cells within a particular metastatic site and then validate expression of candidate genes and gene products in additional breast cancer samples (both primary tumor and metastases) and follow up with functional studies in our cell-based and mouse models.


Dr. Siegel’s recent publications