Although the area of tumor cell dissemination via angiogenesis is a fertile area of research, translating into the development of anti-angiogenesis therapies, we now recognize that the lymphatic vascular system also provides a deadly conduit for the spread of cancerous cells to distant sites.
However, our relatively poor understanding of factors that regulate lymphatic vessel development and/or function has severely hindered our progress toward identifying pharmacological targets for lymphatics.
The major challenges that are impeding our ability to effectively target the lymphatic vasculature for the inhibition of tumor metastasis are i) lack of information regarding genes and signaling pathways important for lymphangiogenesis, ii) lack of appropriate mouse models to study lymphatic metastasis and iii) lack of suitable pharmacological targets and compounds for the modulation of lymphatic growth or function.
We have identified a unique G protein-coupled receptor (GPCR) signaling cascade for the adrenomedullin peptide that is required for developmental lymphangiogenesis and is upregulated in a subset of human cancers that have distal metastasis and poor prognosis. We have further shown that genetic titration of adrenomedullin in an in vivo tumor model is directly correlated with tumor and sentinel lymph node lymphangiogenesis, as well as lung metastasis.
Our goals are to elucidate the mechanisms through which this signaling paradigm drives tumor lymphangiogenesis and to screen for small molecule interrogators that specifically target this unique GPCR signaling cascade. Positive results from our proposed studies will remarkably advance our basic understanding of tumor metastasis through lymphatics and identify new avenues for cancer therapy.