Tumor-induced bone disease frequently occurs in patients suffering from some of the most common malignancies (prostate, breast, lung) in the general population and the Veteran population. While the tumor microenvironment is known to support tumor growth and bone destruction, the details of these interactions remain unclear. Despite the well-defined role of bone marrow derived cells in supporting tumor growth and metastasis in soft tissue sites, surprisingly little is known about their contribution to tumors residing in the bone. Our group has previously demonstrated that Myeloid Derived Suppressor Cells expand over time as tumors grow in bone, and our preliminary data show that myeloid cells can infiltrate into tumors residing in bone. Other groups have suggested that these infiltrating myeloid cells can support tumor growth directly through the secretion of tumor promoting factors and indirectly by inhibiting the innate immune response, thereby allowing the tumor to ?hide? from immune detection. However, little is known about the immune repressive function of these cells in bone metastatic disease. Because of the importance of the innate immune response for the detection of tumors, many groups have begun testing the utility of innate immune activators as a therapy for reducing tumor in soft tissue, but this has not been explored in TIBD. Our preliminary data show that STING can stimulate an innate immune response and re-polarize bone marrow derived macrophages to a more immune-stimulating phenotype, thus suggesting a potential therapeutic approach for shifting the infiltrating myeloid cells from tumor promoting to tumor inhibiting. We hypothesize that 1) Infiltrating myeloid cells support tumor growth in bone directly by altering tumor gene expression and by inhibiting anti-tumor innate immune responses and 2) that innate immune activation via the STING pathway will shift infiltrating myeloid cells from a pro-tumor to an anti-tumor phenotype that reduces tumor-induced bone disease. In order to address these hypotheses, we propose to 1) Investigate the function of infiltrating myeloid cells in promoting tumor growth in bone, 2) Determine if activation of the STING pathway repolarizes tumor infiltrating myeloid populations towards an antitumor phenotype, and 3) Determine the effect of STING activation on tumor-induced bone disease.
These aims will help further define the role of infiltrating myeloid cells and determine whether STING activation can reduce these infiltrating cells or reprogram them to induce an anti-tumor immune response to reduce TIBD.
Bone marrow derived cells are known to be important contributors of tumor progression in many different tumor types. However, little is known regarding to their contributions in tumor-induced bone disease (TIBD). Despite the fact that patients frequently develop bone metastatic disease which severely impacts length and quality of life, there are no cures. Thus, new therapeutics are needed to treat patients with bone metastatic disease. In this study, we will examine the role of infiltrating myeloid cells in supporting tumor growth in bone and bone destruction, both directly and by repressing an anti-tumor immune response. We will further examine if activating an immune response by activating STING, an immune activating pathway, can reduce tumor growth in bone and bone destruction. These studies will help contribute to our understanding of the tumor-bone microenvironment and may lead to successful therapies for treating Veterans with bone metastatic disease.
|Buenrostro, Denise; Kwakwa, Kristin A; Putnam, Nicole E et al. (2018) Early TGF-? inhibition in mice reduces the incidence of breast cancer induced bone disease in a myeloid dependent manner. Bone 113:77-88|
|Kwakwa, Kristin A; Sterling, Julie A (2017) Integrin ?v?3 Signaling in Tumor-Induced Bone Disease. Cancers (Basel) 9:|
|Mulcrone, Patrick L; Campbell, J Preston; Clément-Demange, Lise et al. (2017) Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and ?2AR-Dependent Neo-Angiogenic Switch. J Bone Miner Res 32:1442-1454|
|Vanderburgh, Joseph; Sterling, Julie A; Guelcher, Scott A (2017) 3D Printing of Tissue Engineered Constructs for In Vitro Modeling of Disease Progression and Drug Screening. Ann Biomed Eng 45:164-179|
|Vanderburgh, Joseph P; Fernando, Shanik J; Merkel, Alyssa R et al. (2017) Fabrication of Trabecular Bone-Templated Tissue-Engineered Constructs by 3D Inkjet Printing. Adv Healthc Mater 6:|
|Kwakwa, Kristin A; Vanderburgh, Joseph P; Guelcher, Scott A et al. (2017) Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments. Curr Osteoporos Rep 15:247-254|
|Johnson, Rachelle W; Finger, Elizabeth C; Olcina, Monica M et al. (2016) Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 18:1078-1089|
|Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar et al. (2016) Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease. Bone 91:81-91|
|Wright, Laura E; Ottewell, Penelope D; Rucci, Nadia et al. (2016) Murine models of breast cancer bone metastasis. Bonekey Rep 5:804|
|Guo, R; Lu, S; Merkel, A R et al. (2016) Substrate Modulus Regulates Osteogenic Differentiation of Rat Mesenchymal Stem Cells through Integrin ?1 and BMP Receptor Type IA. J Mater Chem B 4:3584-3593|
Showing the most recent 10 out of 26 publications