UC San Diego

The tumor microenvironment plays a critical role in dictating cancer outcome. Specifically, intercellular communication that occurs between transformed cancer cells and non-transformed host cells is increasingly recognized as a critical regulator of many processes related to cancer, including progression, regression, drug resistance, and metastasis. In this dissertation, we have investigated to role of 2 independent mechanisms of intercellular communication in cancer: exosomes and cell-cell fusion.

Exosomes are small membrane vesicles of endosomal origin that mediate intercellular communication via the transfer of bioactive cargo to target cells. Cancer cells abundantly produce exosomes, and tumor-derived (TD) exosomes are now appreciated as major forces capable of modulating the properties of host cells, including immune cells. Here, we discovered that the signaling molecule

MAP2K1 (MEK1) is enriched in exosomes from regressing tumors compared to exosomes from progressively-growing tumors. Moreover, we found that MEK1 protein in exosomes promotes anti-tumor immunity and is sufficient to delay the growth of both syngeneic and 3rd party tumors. These findings have clinical significance since MEK1 inhibitors currently used to treat cancer could have negative consequences by dampening the tumor-suppressive, immunestimulatory effects of MEK1 in exosomes.

Cell-cell fusion was first recognized to occur in cancer over 100 years ago, yet it remains debated whether this phenomenon is physiologically relevant to disease progression. Here, we serendipitously developed a model system that could observe and measure cell-cell fusion in cancer. We found that cancer cells spontaneously and rapidly fuse with non-cancer cells, and the resulting hybrid cells possess enhanced chemoresistance and a higher degree of heterogeneity/ clonal diversity compared to parental cells. These results imply that cell-cell fusion promotes malignant properties associated with cancer and could serve as an engine to drive cancer cell diversification, thus providing the substrate for cancer cell evolution.

The studies presented in this dissertation add to the growing body of evidence that intercellular communication within the tumor microenvironment has profound effects on many different aspects of cancer, and serve as a reminder that the cell-extrinsic communication occurring between cancer cells and non-cancer cells should be carefully studied to develop novel cancer treatments.