Sunday, November 24, 2024
11/24/2024
Hypoxia and macrophages drive tumor aggressiveness and treatment outcome leading to worse prognosis for breast cancer patients. Contrary to acute hypoxia where tissue homeostasis is vital for development and repair, chronic hypoxia observed in solid tumors stimulate unproductive angiogenesis by excessive vascular endothelial growth factor expression leading to dysfunctional vessels that perpetuate hypoxia and acidic extracellular pH; factors that limit effective perfusion of treatment modalities like chemotherapies and radiotherapies and promote tumor aggressiveness. Macrophages are intimately involved in regulating unproductive angiogenesis thru secretion of soluble factors that support this activity. In the parent grant, we advanced electron paramagnetic resonance (EPR)-based techniques towards in vivo real-time tumor microenvironment (TME) profiling in animal cancer models. Using these approaches, we showed macrophage hypoxia-inducible transcription factors (HIF)- 1α and HIF-2α had disparate roles in regulating TME parameters like oxygen and pHe through structural and functional alterations in vessels that dictated docetaxel efficacy. We showed that HIF-1α augments expression of endothelial tyrosine kinase (TIE2) receptor on macrophages called TIE2-expressing macrophages (TEMs) previously-reported to be “pro-angiogenic”, but now better defined as “pro-hypoxic” by dysregulating vessels leading to poor perfusion. The overall objective of the renewal is to investigate macrophage location and function that perpetuates a hypoxic TME detrimental to perfusion of therapeutic modalities. To achieve this central objective, we propose these specific aims: (SA1): To optimize magnetic resonance imaging modalities for in vivo multifunctional mapping of local tumor tissue parameters. Advances in paramagnetic probes and imaging technologies such as rapid scan EPR imaging and Overhauser-enhanced MRI allow for mapping specific areas of hypoxia and acidosis and characterizing their relationship to tumor macrophage locoregional populations. (SA2): Elucidate tumor macrophage location-specific functions in regulating hypoxia and acidosis in a mouse model of breast cancer. We will sample tumor origin and regions of hypoxia in PyMT breast cancer models using image-guided biopsy to understand the bi-directional shaping of TME and macrophages that contribute to poor vessel perfusion and hypoxia. (SA3): Investigate recruited and tissue- resident macrophage populations and their respective roles in contributing to tumor hypoxia and acidosis that dictate chemotherapy effectiveness. We will track fluorescent bone marrow monocytes to tumor origin, and generate conditional macrophage-deficient breast tumor mice to systematically determine a causal role of specific macrophage populations. Summarizing, in vivo mapping of tumor hypoxia and acidosis using innovative magnetic resonance technology in mice deficient in specific macrophage populations or lacking hypoxia-regulated macrophage functions in a mouse model of breast cancer may provide new insight into a macrophage/TME axis that suppresses the efficacy of clinically-relevant anti-cancer therapies.
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).
