UCSF

Metastasis is a major cause of cancer mortality among patients with breast cancer. Currently, limited options exist for treatment of metastatic disease, none of which are specific to the various changes that tumor cells undergo as they journey from the primary tumor to a distant metastatic site. This dissertation explores mechanisms central to breast cancer metastasis to the lung through tumor cell-intrinsic and -extrinsic lenses. In chapter 1, we present an overview of breast cancer metastasis, the foundational studies that led to what is now known as the “metastatic cascade”, and a current perspective on tumor-intrinsic and -extrinsic mechanisms that can be targeted to treat metastasis which will be the focus of this dissertation. In chapter 2, we test two hypotheses about how pro- and anti-metastatic myeloid phenotypes arise in breast cancer: (1) that pro- and anti-metastatic myeloid microenvironments are discrete and unique, and (2) that pro- and anti-metastatic myeloid microenvironments are two ends of a spectrum of metastatic development. We profiled 12 differently metastatic patient-derived xenograft (PDX) models and discovered that distinct monocyte phenotypes dominate lowly and highly metastatic PDX models. However, we also find that anti-metastatic monocytes are present at early timepoints in highly metastatic tumor models and progressively shift towards a pro-metastatic phenotype. This work demonstrates that there is a window within the metastatic cascade where the lung myeloid microenvironment could be harnessed to suppress metastasis. In chapter 3, we explore a tumor cell-intrinsic approach to suppressing metastasis by investigating the effect of exposure to increased oxygen (“hyperoxia”) on breast cancer metastasis to the lung. We find that hyperoxia depletes electron transport chain subunits, and subsequently leads to a decrease in proliferation, anchorage independent colony-forming ability, and strikingly, spontaneous metastasis to the lung. Collectively, these two studies uncover promising susceptibilities of metastasis that merit further evaluation.