Massachusetts Institute of Technology
Cambridge, Massachusetts
Member, Whitehead Institute Director, Ludwig Center for Molecular Oncology Daniel K. Ludwig Professor for Cancer Research
Uncovering what triggers dormant breast cancer cells to become active and cause disease recurrence.
The majority of primary breast tumors are successfully cured, but delayed recurrence of disease – years or decades after diagnosis—occurs in as many as 30 percent of initially treated patients. A significant proportion of these relapses arise from cancer cells that left the primary tumor and seeded other sites such as the lungs, liver, bone marrow, and even the brain. These micro-metastases are “dormant,” in that they give no clinical sign of active disease. Dr. Weinberg is examining the biology of these dormant cells and the mechanisms that provoke their “awakening” and lead to breast cancer metastasis. Understanding this process will provide new insight into how and why disseminated cancer cells that lie dormant suddenly become activated to generate life-threatening metastases in patients who are seemingly disease-free.
Dr. Weinberg’s research has shown that “awakening” of dormant cancer cells can arise under the pressure of an inflammatory state that promotes their proliferation. He and his team have found that M2 macrophages, a tumor promoting immune cell, release a specific protein that signals growth and stimulates dormant breast cancer cells. The team revealed that this begins to drive the previously dormant cancer cells into an actively proliferating state in which they can persist even without the inflammatory macrophages. Further experiments have led them to determine that while the M2 macrophage is essential in re-emergence of dormant tumor cells other factors are also required for full-fledged activation.
Dr. Weinberg’s upcoming work will further explore cancer cell dormancy and awakening. First, he and his team will assess whether collaborating immune cells around the dormant cancer cells are critical players in the awakening process of M2 macrophages. Second, the team will analyze whether the mechanisms of inflammation-driven awakening are general to multiple sites of metastasis, including liver and bone marrow, or whether they are unique to the site. Third, Dr. Weinberg and his team will explore whether awakened breast cancer cells undergo genetic changes. Further validation of the characteristics of dormant cancer cells and the processes they undergo to become awakened could potentially improve the clinical early detection, targeting, and elimination of dormant cancer cells before they are awakened.
Dr. Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology (MIT) and the first Director of the Ludwig Cancer Center at MIT. He is an internationally recognized authority on the genetic basis of human cancer. Dr. Weinberg’s team isolated the first human cancer-causing gene, the ras oncogene, and the first known tumor suppressor gene, Rb, the retinoblastoma gene.
Research in Dr. Weinberg’s laboratory is focused on attempting to elucidate the biochemical and cell-biological mechanisms that enable carcinoma cells in primary tumors to invade and disseminate, resulting in the formation of metastases in distant sites. Much of this work depends on analyses of the cell-biological program termed the epithelial-mesenchymal transition (EMT). In addition to conferring traits such as motility and invasiveness on epithelial carcinoma cells, activation of this program heightens their resistance to chemotherapeutic attack. In recent years, the Weinberg laboratory has also found that activation of a previously latent EMT program places both normal and neoplastic epithelial cells in a position from which they can enter into a stem cell state. In the case of carcinomas, the tumor-initiating powers resulting from this shift indicates the formation of cancer stem cells (CSCs), which are qualified to serve as founders of new metastatic colonies in distant anatomical sites. Dr. Weinberg’s research has increasingly focused on the interaction of CSCs with recruited inflammatory cells and on the later steps of the invasion-metastasis cascade that enables disseminated carcinoma cells to extravasate, thereby setting the stage for the formation of micro- and macroscopic metastatic colonies.
2003
The Hale Family Award
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