|Jayanta Debnath, M.D.|
|University of California San Francisco|
Deconstructing the self-cannibalization of cells to head off metastasis in breast cancer.
The most common human cancers, such as those in the breast, prostate, and colon, arise from epithelial cells; tumors of epithelial origin are collectively called carcinomas. The lethality of these cancers is primarily due to the fact that carcinoma cells are able to invade, disseminate and form metastases throughout the body.
Two hallmarks distinguish carcinomas that exhibit these aggressive behaviors in human patients:
1) In order to metastasize to foreign tissue sites, tumor cells must to adapt and survive diverse micro-environmental stresses and barriers.
2) To invade and disseminate throughout the body, carcinoma cells must inhibit the cardinal features of normal epithelial differentiation, such as the ability to form strong cell-cell contacts and organize into well-ordered glandular structures.
The goal: By identifying the pathways used by tumor cells to survive adverse stresses and to invade surrounding tissue, we may develop innovative strategies to prevent metastasis and reduce the lethality of epithelial cancers.
Dr. Debnath’s research project proposes that one important therapeutic target is a fundamental cellular stress response pathway, called autophagy, because it promotes both carcinoma survival and invasion. Autophagy is literally the process of cellular “self-eating,” that is, cells digest small bits and pieces of themselves and recycle the resulting nutrients in order to survive starvation or stress. We previously showed that autophagy is robustly induced as a survival pathway in carcinoma cells deprived of extracellular matrix (ECM) contact; this finding has important clinical implications because the unique ability of carcinoma cells to survive in the absence of proper extracellular matrix (ECM) contact is a critical feature of metastasis. In addition to our work, other labs have demonstrated autophagy as a survival pathway in cancer cells, which altogether, has motivated immense interest in targeting autophagy to thwart the development of aggressive and lethal carcinomas.
In addition to the growing evidence that autophagy functions as a survival pathway in cancer, Dr. Debnath’s lab has recently uncovered a novel function for autophagy in promoting tumor cell invasion. Inhibiting autophagy in oncogenic cells profoundly diminishes their ability to invade the surrounding tissue and restores several aspects of normal epithelial differentiation, including the ability to form cell-cell junctions. In addition, autophagy inhibition significantly reduces metastasis in vivo.
In further work, the Debnath team has discovered that these defects in invasion and metastasis found in autophagy-defective cells are due to the impaired secretion of multiple critical factors favoring invasion, including the diminished secretion of a well-known, pro-invasive molecule called interleukin-6 (IL6). Overall, their findings reveal an unexpected role for autophagy in facilitating secretion during tumor cell invasion. Accordingly, they propose that inhibiting autophagy in carcinoma cells will not only predispose them to cell death when they are exposed to stress, but will impede their ability to secrete the factors that are critical for their ability to invade and disseminate to foreign sites.
Dr. Debnath and his team will further test and refine the hypothesis that autophagy-dependent secretion promotes the aggressive behavior of carcinoma cells.
From a therapeutic standpoint, his long-term objective is to determine whether and how autophagy inhibition can be most effectively exploited as “an Achilles heel” to prevent cancer’s progression and metastasis.