Age is a significant risk factor for the development of cancer. The mechanisms that drive this risk are complex and involve both the accumulation of cell autonomous mutations within incipient tumor cells and pro-tumorigenic changes in the tumor microenvironment. Investigation into the impact of an aging microenvironment on tumorigenesis has revealed that senescent stromal cells can directly stimulate preneoplastic and neoplastic growth. Because senescent cells accumulate with age, these observations raise the possibility that senescent cells are an important contributor to age-related increases in tumorigenesis. To understand how senescent stromal cells contribute to tumorigenesis, we developed the FASST mouse (Fibroblasts Accelerate Stromal- Supported Tumorigenesis) that allows us to control the spatial and temporal activation of senescence in mesenchymal cells. Using this mouse, we found that senescent mouse skin fibroblasts (MSFs) support increased tumorigenesis in immunocompetent mice. Strikingly, we found that MSFs that arise independently of neoplastic cells mediate their pro-tumorigenic properties by modulating the host immune system and creating immunosuppression that limits CD8 T cell activity, thus allowing increased tumor growth. Previous work has focused on the ability of senescent fibroblasts to directly stimulate tumor cell growth. Thus our work is the first to show that senescent MSFs can promote tumor growth by modulating the immune system. Because we find that senescent MSFs in our model cause localized recruitment of immunosuppressive cells, similar to what we find in aging human skin, we propose that they contribute to age-related increases in tumorigenesis by creating regions of local immune suppression that shelter incipient tumor cells and allow their outgrowth. To understand the dynamics of immune modulation in the FASST model, we propose to determine the temporal pattern of immune cell infiltration, the mechanisms that drive immune cell infiltration, and the senescence-specific factors that drive the development and maintenance of the suppressive microenvironment present in the FASST mouse. Further we propose to examine the impact of senescent stromal cells on a spontaneous model of squamous cell carcinoma (SCC, K14-HPV16) where 100% of animals develop hyperplasia yet only 20% convert to SCC. Here we propose that the activation of senescence within the stromal compartment will increase the penetrance in this model by altering the immune landscape. Finally, we will ask how p38MAPK-dependent senescence-associated secretory phenotype (SASP) factors contribute to the immunosuppressive environment created by senescent stromal cells and ask in a preclinical setting if targeting p38MAPK or its downstream kinase MK2 is a valid approach to reducing senescent stromal-supported tumorigenesis. Data from this proposal will provide vital mechanistic insight and novel therapeutic targets that may reduce age-related increases in cancer.
Statement Age is a significant risk factor for the development of cancer. We recently found that in addition to increasing tumor cell growth, senescent cells activate proteins that modulate the immune system and create an atmosphere of immune suppression that allows tumor cells to grow unabated. We will explore the impact of inhibition of these key proteins on immune modulation and tumor growth. Identification of these proteins will provide a better understanding of the process and, importantly, may provide novel therapeutic targets.
|Murali, Bhavna; Ren, Qihao; Luo, Xianmin et al. (2018) Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss. Cancer Res 78:5618-5630|