Tissue remodeling is a characteristic of many solid tumor malignancies including melanoma. By virtue of tumor lymphatic transport, remodeling pathways active within the local tumor microenvironment have the potential to be operational within lymph nodes (LNs) draining the tumor interstitium. Here, we show that lymphatic drainage from murine B16 melanomas in syngeneic, immune-competent C57Bl/6 mice is associated with LN enlargement as well as nonuniform increases in bulk tissue elasticity and viscoelasticity, as measured by the response of whole LNs to compression. These remodeling responses, which quickly manifest in tumor-draining lymph nodes (TDLNs) after tumor inoculation and before apparent metastasis, were accompanied by changes in matrix composition, including up to 3-fold increases in the abundance of soluble collagen and hyaluronic acid. Intranodal pressures were also significantly increased in TDLNs (+1 cmH2O) relative to both non-tumor-draining LNs (-1 cmH2O) and LNs from naive animals (-1 to 2 cmH2O). These data suggest that the reorganization of matrix structure, composition, and fluid microenvironment within LNs associated with tumor lymphatic drainage parallels remodeling seen in primary malignancies and has the potential to regulate the adhesion, proliferation, and signaling function of LN-resident cells involved in directing melanoma disease progression.

Changes in tissue mechanical properties are often the first indication of malignant disease, with the detection of a stiff lump by a patient. These changes include growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow, which in turn enhance fluid flux away from the tumor to downstream lymph nodes (LNs). But in addition to changing the way a tumor feels to a patient, altered tumor tissue mechanics promote cancer cell invasion into lymphatic vessels, allowing their metastatic dissemination to draining LNs. LN swelling and stiffening is another common indicator of tumor growth, and the presence of metastatic cells in the sentinel LN, or tumor draining lymph node (TDLN), is used clinically to stage disease. Recent studies indicate the LN microenvironment determines whether metastatic cancers can spread to the sentinel LNs. Yet despite the known correlation of LN swelling and stiffening with tumorigenesis and the role of the LN microenvironment in metastasis, our understanding of how changes in LN mechanical properties relate to tumor progression, anti-tumor immune response and metastatic colonization of the LN is limited. This lack of a quantitative understanding limits functional analyses of the role of LN mechanics in determining cancer cell colonization of the TDLN, their influence on immune suppression taking place within the TDLN, as well as the development of strategies to mitigate these effects.