Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation

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DESCRIPTION (provided by applicant): Age-related changes in the tumor microenvironment are hypothesized to significantly impact tumorigenesis. Investigation into how age contributes to increased cancer incidence has focused on accumulation of autonomous mutations within incipient cancer cells. While it is clear that these mutations are integral to the transformation process, it is now well accepted that the surrounding stroma collaborates in the process and thus contributes to age-dependent increases in cancer incidence. Indeed, "normal" fibroblasts within a tumor secrete factors that promote tumor cell growth. Like genetic mutations, senescent fibroblasts accumulate with age, and recent data suggests that they promote tumorigenesis. We hypothesize that as the number of senescent fibroblasts increase within the stromal compartment with age, they create a pro-tumorigenic environment that promotes tumorigenesis. To test this hypothesis, we created the "FASST" (fibroblasts accelerate stromal-supported tumorigenesis) mouse, which is a novel model that allows us to temporally and spatially control the activation of senescence in the stromal compartment of a young mouse and ask how this impacts tumor latency, penetrance and progression. Using the FASST model, we show that the presence of senescent stroma in young animals accelerates the appearance of papillomas following a classic two-step skin carcinogenesis protocol. The goal of this proposal is to elucidate the mechanisms by which senescent stroma promotes tumorigenesis. First, we will determine if senescence accelerates tumorigenesis by acting locally and/or systemically. Because we have already demonstrated that osteopontin (OPN) is an important senescent stromal-derived factor in the skin, we will focus on OPN and its ability to stimulate preneoplastic cell proliferation directly and its ability elicit a pro-tumor inflammatory response and determine how this impacts tumorigenesis in the FASST model. Finally, we expand these studies to include analysis of tumorigenesis in the breast, which allows us to ask a critical question; does senescence create a general pro-tumorigenic state or is its activities tissue and oncogene specific? The data provided by these questions will shape our general understanding of tumorigenesis and may lead to the identification of novel stromal-specific therapeutic targets. The specific aims of this proposal are: Aim 1: Determine whether cancer promotion by senescent stromal cells acts locally or systemically in a well-characterized two-step skin carcinogenesis model Aim 2: Identify the OPN dependent and independent mechanisms by which senescent stroma accelerate tumorigenesis Aim 3: Determine the tumor-promoting abilities of senescent stroma on breast tumorigenesis. PUBLIC HEALTH RELEVANCE: Age is the largest risk factor for the development of cancer. Therefore, understanding the age-related changes that impact cancer development will increase our understanding of the process and supply us with better medical interventions. This project proposes to study how changes in the normal cells that surround a tumor (referred to as stromal cells) influence tumor development. To this end, we have developed an animal model (referred to as the FASST model) that recapitulates many of the features of human aging within this stromal compartment. This model will be used to determine how age-related changes in non-tumor cells promote tumor growth. Information gained from these studies may identify novel therapeutic targets.