Leveraging the metastatic tumor stroma to limit breast cancer progression

Project Abstract Over 297,790 new cases of invasive breast cancer diagnoses and 43,170 deaths from metastatic breast cancer (mBC) are expected in the USA this year (SEER database). Despite advances in the treatment of localized disease, the 5-year overall survival of patients with mBC remains at a dismal 29%. Current therapeutic strategies

primarily focus on tumor cells and neglect the important role the tumor stroma plays in cancer progression. Underscoring the importance of the stromal compartment, stromal gene signatures can predict clinical outcomes for breast cancer patients7. The most common site of breast cancer metastasis is the bone and unfortunately,

once the disease metastasizes to the bone, it is considered incurable and treatment is mainly palliative8. In the bone, the tumor stroma consists of a wide array of cell types including fibroblasts, adipocytes, nerve cells, endothelial cells, immune cells, chondrocytes, osteocytes, osteoblasts, and osteoclasts. Nearly all of these

stromal cell types has been implicated in tumor progression by directly supporting tumor cell growth, survival, modulating the immune response to tumors, and/or driving bone loss that ignites a vicious cycle that supports further tumor growth in the bone8. One important stromal cell that supports primary tumor progression is the

senescent cell, which was recently described as an emerging cancer hallmark9. Indeed, we demonstrated that senescent fibroblasts drive tumor growth10 and create immunosuppressive environments11 in the primary tumor setting through expression of p38MAPKα-dependent senescence associated secretory phenotype (SASP)

factors. Whether the same mechanisms are active in the metastatic setting remains an open question. We have found that p38MAPKα inhibition (p38i) reduces mBC progression by targeting the metastatic stromal compartment, but not tumor cells, in numerous preclinical models. In this proposal, we will examine how

p38MAPKα activation in the metastatic stroma contributes to tumor progression and modifies the immune response to allow mBC to progress. We will utilize genetic and pharmacologic tools to identify the cell targets of p38i, determine if a new stromal cell that we have identified, the senescent metastatic-associated cancer

associated fibroblast (smeCAF) contributes to cancer-induced bone loss, and determine if smeCAFs modify the host immune response within the bone. Our goal is to understand how p38i alters the stromal compartment to decrease mBC progression so that this knowledge can be leveraged to develop combinatorial strategies to

deploy p38i, senolytics (drugs that kill senescent cells), and immunotherapy to limit mBC progression.