Faculty Bibliography

The lymphatic system is a complicated system consisting of the lymphatic vessels and lymph nodes draining the extracellular fluid containing cellular debris, excess water and toxins to the circulatory system. The lymph nodes serve as a filter, thus, when the lymph fluid returns to the heart, it is completely sterile. In addition, the lymphatic system includes the mucosa-associated lymphoid tissue, such as tonsils, adenoids, Peyers patches in the small bowel and even the appendix. Taking advantage of the drainage system of the lymphatics, cancer cells enter the lymphatic vessels and then the lymph nodes. In general, the lymph nodes may serve as a gateway in the majority of cases in early cancer. Occasionally, the cancer cells may enter the blood vessels. This review article emphasizes the structural integrity of the lymphatic system through which cancer cells may spread. Using melanoma and breast cancer sentinel lymph node model systems, the spread of early cancer through the lymphatic system is progressive in a majority of cases. The lymphatic systems of the internal organs are much more complicated and difficult to study. Knowledge from melanoma and breast cancer spread to the sentinel lymph node may establish the basic principles of cancer metastasis. The goal of this review article is to emphasize the complexity of the lymphatic system. To date, the molecular mechanisms of cancer spread from the cancer microenvironment to the sentinel lymph node and distant sites are still poorly understood and their elucidation should take major priority in cancer metastasis research.

Vascular normalization therapy has the potential to facilitate drug delivery and lymphocyte infiltration in tumors. Yet, optimal targets and dosage regimens remain elusive. In this issue of Med, O'Connor et al. show that inhibition of LRG1 stabilizes the tumor-associated vasculature to enhance tumor response to both cytotoxic and immune therapies.

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Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

Despite advances in melanoma treatment, more than 70% of patients with distant metastasis die within 5 years. Proactive treatment of early melanoma to prevent metastasis could save lives and reduce overall healthcare costs. Currently, there are no treatments specifically designed to prevent early melanoma from progressing to metastasis. We used the Connectivity Map to conduct an in silico drug screen and identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) as a drug class that might prevent melanoma metastasis. To confirm the in vitro effect of statins, RNA sequencing was completed on A375 cells after treatment with fluvastatin to describe changes in the melanoma transcriptome. Statins induced differential expression in genes associated with metastasis and are used in commercially available prognostic tests for melanoma metastasis. Finally, we completed a chart review of 475 patients with melanoma. Patients taking statins were less likely to have metastasis at the time of melanoma diagnosis in both univariate and multivariate analyses (24.7% taking statins vs. 37.6% not taking statins, absolute risk reduction = 12.9%, P = 0.038). These findings suggest that statins might be useful as a treatment to prevent melanoma metastasis. Prospective trials are required to verify our findings and to determine the mechanism of metastasis prevention.

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

A new cancer vaccine technology builds a network of local lymphatic vessels that paves the way to stronger responses to immunotherapy.

Lymphatic vessels provide an anatomical framework for immune surveillance and adaptive immune responses. Although appreciated as the route for Ag and dendritic cell transport, peripheral lymphatic vessels are often not considered active players in immune surveillance. Lymphatic vessels, however, integrate contextual cues that directly regulate transport, including changes in intrinsic pumping and capillary remodeling, and express a dynamic repertoire of inflammatory chemokines and adhesion molecules that facilitates leukocyte egress out of inflamed tissue. These mechanisms together contribute to the course of peripheral tissue immunity. In this review, we focus on context-dependent mechanisms that regulate fluid and cellular transport out of peripheral nonlymphoid tissues to provide a framework for understanding the effects of afferent lymphatic transport on immune surveillance, peripheral tissue inflammation, and adaptive immunity.

Lymph nodes are typically the first clinically detectable site of metastasis in melanoma, but the mechanisms that determine this preference are not well understood. An article in Nature reports that the unique composition of lymph may protect melanoma cells from ferroptosis-a form of iron-dependent cell death, thereby increasing metastatic efficiency.