Skeletal muscle: an exploration into an anti-metastatic niche and the molecular mechanisms that underlie it

Abstract

Over the past four decades, the cancer biology field has concentrated on defining the molecular basis of metastasis by characterizing changes to extracellular microenvironments of disseminated tumor cells that promote metastatic outgrowth in organs such as the lung, liver and bone. However, clinical reports highlight that patterns of metastatic dissemination are not random nor equal across all tissues in the body. If not all tissues are equally susceptible to metastatic colonization, what distinguishes a tissue that is resistant from another that is permissive? What constitutes an inhospitable microenvironment? My doctoral work aimed to address this gap in our knowledge by using skeletal muscle as a model for an anti-metastatic tissue. I employed mouse and organotypic culture models, along with metabolomics and proteomics, to identify i) a niche for disseminated tumor cells within skeletal muscle, ii) metabolic factors within this tissue microenvironment that inhibit outgrowth of breast and mammary cancer cells, and iii) a potential mechanism by which extracellular matrix remodeling breaks suppression. Together, these approaches identify sustained oxidative stress as a critical determinant of disseminated tumor cell suppression in skeletal muscle, and peritumoral collagen accumulation as a key promoter of disseminated tumor cell outgrowth.