CAREER: Cancer-associated secondary lymphedema on-chip

Lymphedema is swelling caused by poor lymphatic drainage. In the US, breast cancer patients show a high incidence of lymphedema in their arms. The goals of this CAREER project are to comprehend the regulation of the lymphatic structure and function in breast cancer and to discover novel approaches to treating lymphedema linked to breast cancer through the establishment of a unique cell culture platform dedicated to studying lymphatic drainage in breast cancer.

This project may contribute to the development of new therapies benefitting millions of lymphedema patients and enhancing health outcomes in the US. Educational initiatives involving Cornell and local high school students are aligned with the research goals. The recruitment and training of a diverse group of underrepresented undergraduate students will be carried out through Cornell Engineering Learning Initiatives and the Prefreshman Summer Program.

Collaborations with New Visions Engineering and the Cornell Science and Technology Entry Program will further engage disadvantaged high school students in hands-on activities related to lymphatic research. Additionally, the project's educational program will create online courses to raise scientific awareness of lymphatic diseases.

Lymphedema, characterized by swelling due to impaired lymphatic drainage, affects over 150 million patients worldwide. Despite its prevalence, there is no FDA-approved treatment, and commonly used conservative therapies provide primarily palliative relief. This CAREER project seeks to investigate the mechanisms of lymphedema, identifying potential therapeutic targets and treatment strategies.

While genetic defects can cause primary lymphedema, secondary lymphedema, particularly breast cancer-associated secondary lymphedema, is more common. However, the mechanistic understanding of breast cancer-associated secondary lymphedema is currently limited. The lack of experimental models for normal and impaired lymphatic drainage has been a significant obstacle.

The principal investigator addresses this challenge with a microfluidic culture model featuring an engineered lymphatic vessel that mimics key lymphatic endothelial cell-cell junctions. These junctions are crucial for facilitating lymphatic drainage and allow for the study of how they are affected in conditions such as breast cancer. The project extends this work by creating tissue-engineered co-culture models replicating the breast tumor lymphatic microenvironment.

These models involve culturing multiple breast tumor cells and lymphatic cells in a well-defined three-dimensional space outside living organisms. A pilot study revealed that triple-negative breast cancer cells impact lymphatic structure and function, leading to impaired drainage. The research is organized into two specific aims: Aim 1 focuses on understanding the regulation of lymphatic junction structure and drainage function in breast cancer and Aim 2 centers on the treatment of breast cancer-associated secondary lymphedema.

In conjunction with educational outreach, this CAREER project will contribute to the development of new therapies for lymphedema patients in the US and will enhance scientific awareness of lymphatic disease and microphysiological systems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.