Sheila A. Stewart, Ph.D.

Associate Professor
Cell Biology and Physiology

Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Biochemistry, Biophysics, and Structural Biology Program
Computational and Systems Biology Program

  • 314-362-7437

  • 314-362-7449

  • 314-362-7463

  • 8228

  • 7610 BJC-IH BRIGHT Institute



  • aging, cancer, microenvironment, RNAi, senescence, telomere

  • Examining the role the tumor microenvironment plays in immune modulation, tumor development, metastasis and dormancy

Research Abstract:

Our research is focused on understanding how age-related changes in the tumor microenvironment contribute to tumorigenesis including progression and the development of a conducive pre-metastatic niche. This work has led to the finding that senescent-associated stromal OPN promotes tumorigenesis. Given the importance of the OPN and other factors secreted by senescent cells (collectively referred to as the senescence associated secretory phenotype, SASP) we have investigated how the SASP is regulated. This work uncovered a potent post-transcriptional mechanism that is governed by p38MAPK. Indeed, we found that inhibition of p38MAPK reduces SASP expression and results in reduced tumorigenesis. Thus, p38MAPK is an important stromal-specific therapeutic target. In addition, this work has led to the development of a novel animal model (fibroblasts accelerate stromal supported tumorigenesis, FASST) in which old stroma is conditionally activated in a young animal. The development of the FASST model will have a profound impact on our understanding of tumorigenesis by creating a model that more closely approximates the human system. Indeed, the FASST model allows us to spatially and temporarily control the activation of senescence in a young mouse. Importantly, with this model we are examining how a critical component of tumorigenesis, age, impacts the stromal compartment by allowing us to delineate the putative role senescent fibroblasts play in tumorigenesis. Using this model we find that the presence of senescent cells within the bone increase breast cancer metastasis. Because these senescent cells express a plethora of pro-inflammatory factors and recruit myeloid derived suppressor cells, we posit that the increased bone metastasis is due to the creation of an immune-suppressive microenvironment that allows cancer cells to grow unabated. Further we have demonstrated that SASP drives increases in local osteoclastogenesis and tumor cell seeding to regions with senescent osteoblasts. Together these mechanisms increase tumor burden in the bone. This platform has set the stage for us to address a number of significant questions about how the stromal compartment drives the metastatic process.

Bone metastasis is a key determinant of long-term survival and quality of life for breast cancer patients. Despite the fact that the majority of breast cancer cases are diagnosed early, approximately 10-20% recur in patients previously “cured”, demonstrating that primary disseminated tumor cells (DTCs) metastasize early and remain dormant in distant sites only to awaken years later. Indeed, approximately 50% of patients harbor DTCs in their bone marrow and among metastatic sites, bone metastasis is the most common site and correlates with reduced survival and quality of life. Given the large percentage of patients who return to the clinic years after their initial “cure”, and the sad fact that treatment options are limited or only palliative, uncovering the mechanisms that protect dormant DTCs and allow their eventual outgrowth will have a profound impact on the development of novel therapies and patient outcome. We are now investigating the role of senescent stromal in the seeding and emergence of dormant DTCs using the FASST model.

Our current focus areas are:
• The role of senescent stroma in the modulation of the local immune response and its impact on tumor progression
• The impact of senescent bone cells in breast cancer tumor cell dormancy and progression to life threatening lesions
• The role of senescent stromal cells on chemotherapy-induced bone loss
• The role of senescence in the development of a chemoprotective niche
• The therapeutic value of p38MAPK/MK2 inhibition in limiting metastatic progression
• The role of an aging immune system in the control of tumor dormancy

Selected Publications:

Complete List of Published Work in MyBibliography:

Pazolli, E., Luo, X., Brehm, S., Carbery, K., Chung, J.J., Prior, J.L., Doherty, J., Demehri, S., Salavaggione, L., Piwnica-Worms, D., Stewart, S.A. Senescent stromal-derived osteopontin promotes preneoplastic cell growth. Cancer Res. 69:1230-1239. 2009. PMCID: PMC2633422.

Luo X, Ruhland MK, Pazolli E, Lind AC, Stewart SA. Senescent-associated Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway. Mol. Can. Res. 9:1018-1029. 2011. PMCID: PMC3685505.

Pazolli, E., Alspach, E., Milczarek, A. Julie Prior, David Piwnica-Worms and Stewart, S. A. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res. 72(9):2251-61. 2012. PMCID: PMC3605047.

Lee S, Stewart S, Nagtegaal I, Luo J, Wu Y, Colditz G, Medina D, Allred DC. Differentially Expressed Genes Regulating the Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer. Cancer Res. 2012. PMCID: PMC3899801

Saheb-Al-Zamani M, Yan Y, Farber SJ, Hunter DA, Newton P, Wood MD, Stewart SA, Johnson PJ, Mackinnon SE. Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp. Neurol. 247:165-177. 2013. PMCID: PMC3863361

Alspach, E., Flanagan, K. C., Huang, H., Pazolli, E., Donlin, M., and Stewart, S. A. p38MAPK-AUF1 plays a crucial role in stromal-mediated tumorigenesis. Can. Dis. 4:716-729. 2014. PMCID: PMC4049323

Luo, X*., Fu, Y*., Loza, A., Murali, B., Leahy, K., Ruhland, M.K., Gang, M., Su, X., Zamani, A., Shu, Y., Lavine, K.J., Orntiz, D.M., Weilbaecher, K.N., Long, F., Novack, D., Faccio, F., Longmore, G., and Stewart, S. A. Stromal-initiated changes in the bone promote metastatic niche development. Under Revision, Cell Reports.

Flanagan, K. C., Alspach, E., and Stewart, S. A. A role for cmyb in SASP activation. In preparation.

Ruhland MK, Loza, A., Luo, X, Alspach, E, Capietto, A-H., Wielbaecher, K., Longmore, G., Faccio, R., and Stewart, S. A. Senescence-induced immune infiltration promotes age-related tumor development. Under Revision, Nat. Comm.

Saharia A, Guittat L, Lim A, Crocker S, Kulkarni S, Steffen S, Stewart SA. FLAP endonuclease 1 contributes to telomere stability. Current Biology 2008 18: 496-500. PMC2367431.

Saharia A, Stewart SA. FEN1 con contributes to telomere stability in ALT-positive tumor cells. Oncogene 2009 28:1162-1167. PMID: 19137021.

Duxin JP, Dao B, Martinsson P, Rajala N, Guittat L, Campbell JL, Spelbrink JN, Stewart SA. Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol Cell Biol. 2009 29:4274-4282. PMC2715806.

Nittis T, Guittat L, Leduc RD, Dao B, Duxin JP, Rohrs H, Townsend RR, Stewart SA. Revealing novel telomere proteins using in vivo crosslinking,tandem affinity purification and label-free quantitative LC-FTICR-MS. Mol Cell Proteomics 2010 9:1144-1156. PMID: 20097687.

Saharia A, Teasley DC, Chiappinelli KB., Dao B and Stewart SA. FEN1 ensures telomere stability by facilitating replication fork re-initiation. JBC 2010 285(35): 27057-66. PMID: 20551483.

Last Updated: 11/1/2016 11:55:53 AM

Upper: Model of SASP impact on tumorigenesis; Lower: Telomere FISH
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