Our lab focuses on the differential changes that occur during aging in primary microenvironments vs metastatic niches. We have published in melanoma that aged dermal fibroblasts promote a slower-growing melanoma primary tumor compared to a younger microenvironment via secretion of sFRP2, which promotes invasion and dissemination of melanoma cells into the lung. However, aged lung fibroblasts secrete the related family member sFRP1, which acts inversely to sFRP2 by down-regulating dormancy promoting signaling pathways such as Wnt5A and AXL in melanoma cells to promote proliferation and reactivation from dormancy via the MER tyrosine kinase signaling pathway.
We are also focused on uncovering immune specific changes associated with aging in healthy and diseased metastatic niches such as the lung. We hypothesize that the aged lung is able to promote reactivation from dormancy by inducing an immunosuppressive niche via infiltration of Tregs, MDSCs and reducing effector T-cells and other cancer killing immune subtypes. This allows melanoma cells to proliferate unabated by the immune system to promote aggressive metastasis.
Our lab employs in vivo subcutaneous and tail-vein models in young (8 weeks) vs aged (over 52 weeks) mice to assess differences in metastatic outgrowth due to aging (A). Yumm 1.7 melanoma cells metastasize much more aggressively in the aged mouse lung relative to the young mouse lung (B). We are able to employ IHC, CyTOF, spatial transcriptomics and mass spectrometry to identify changes in immune cells and the ECM within these metastatic tumors. We also use young and aged healthy human lung and skin fibroblasts from patients and form 3d reconstructs in the presence of GFP melanoma cells. We can assess growth of these cells in the presence of fibroblasts and FACs sort melanoma and fibroblasts cultures and assess changes at transcriptomic and protein levels.
The Marvin and Concetta Greenberg Pancreatic Cancer Institute at Fox Chase Cancer Center is devoted to advancing pancreatic cancer therapies stemming from rational biological hypotheses, mechanistic investigation, human behavioral influence, community outreach, and early phase clinical trials. As a part of an NCI-designated Comprehensive Cancer, the Institute integrates both basic biological research, clinical medicine, populations science in this effort as well as substantial transdisciplinary research that bridges scientific areas.
