Characterize the tumor microenvironment dynamics in hepatocellular carcinoma (HCC) initiation and progression.
The liver is unique per its capacity to regenerate, and its highly immune-tolerant functions. Kupffer cells (KCs), the tissue resident macrophages of the liver, are critical to maintain liver homeostasis and to promote hepatocyte proliferation during regeneration. Interestingly, KCs share similarities with microglia as their embryological origin (yolk sac), and their high plasticity following tissue injury.
HCCs typically develop in the context of inflamed, injured livers that share traits with chronic regeneration, suggesting that infiltration of innate immune cells occur, as seen during liver regeneration. However, whether the origin of macrophages and the regulation of their function/polarization are connected to their roles in responding to simultaneous inflammation and cancer initiation remains to be determined. Using mouse models of liver regeneration and transposon-based expression of oncogenes/ tumor suppressors relevant to HCC, we hope to determine the spatiotemporal involvement of tissue resident and infiltrating TAMs in HCC progression and recurrence following therapy. We strongly believe that unraveling liver macrophage dynamic pro-tumorigenic functions will allow us to efficiently target their interactions with cancer cells.
Investigating the microenvironmental regulation of glioma recurrence
Not all cells are equally malignant in gliomas. Certain subpopulations are particularly prone to drive resistance and recurrence to chemo- and radiotherapy, through multiple molecular mechanisms including activation of the DNA damage checkpoints or Notch and PARP signaling pathways amongst others. Interestingly, changes in the TME can modulate glioma initiating cells (GICs) response to standard of care treatment through generation of protective niches in the harsh environment of treated tumors. The TME of dormant or recurrent gliomas post-radiation is profoundly changed compared to untreated tumors. Using multiple tracing murine models, we will decipher the role of macrophage in niches of treated and quiescent tumors in order to inhibit their promoting function in favoring emergence of recurrent disease. We hope to unveil some of the fundamental mechanisms behind macrophage interaction with cancer stem cells.
Targeting myeloid cells during glioma therapeutic response to standard of care therapy
The consequences of cancer cell death induced by radio or chemotherapy include the release of endogenous immune adjuvants in the tumor microenvironment (TME) that may influence macrophage activation status and their recruitment to the tumor site. Reciprocally, these polarized macrophages can respond by modulating the resolution of inflammation, the adaptive immune response, and consequently, cancer cell elimination or survival. This create a balance in the TME, where myeloid cells that originally get to the tumor site as a response to inflammation, then can become co-opted or hijacked by cancer cells, and used to their advantage to blunt response to treatment. Our laboratory studies the role of tumor infiltrating bone marrow derived macrophages and tissue resident microglia in glioblastoma multiforme response to standard of care treatment (SoC), using multiple murine models of the disease.
We aim to unravel the dynamic reciprocal interactions between macrophages in the early onsets of radio/chemotherapy response.