Monday, May 13, 2024
5/13/2024
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 p38MAPKa-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 p38MAPKa 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 p38MAPKa 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
