Does tissue architecture drive cancer metastasis?
Metastatic cancer causes >80% of cancer deaths. When cancer moves out of its original location and metastasizes, it also becomes resistant to chemotherapy. Interestingly, some cancers also metastasize and hang out in distant organs like livers and lungs for decades, avoiding detection. There are no good ways to treat metastatic cancers currently. The Raghavan lab hypothesizes that the extracellular matrix architecture of distant organs like livers and lungs promote infiltrative growth of cancer cells. To understand how architecture contributes to cancer metastasis, we employ biomaterial methods to create liver and lung biomatrix scaffolds that retain the architectural elements of those organs. We combine our engineered biomaterials with bioengineered tumor micro-tissues to generate quantifiable metastases that replicated biological processes like epithelial-mesenchymal plasticity, and chemo-resistance. This platform fuels the discovery of new therapeutics to stop metastasis.
Do tissue mechanics drive cancer progression?
Cells (cancer and immune cells) integrate mechanical cues around them into biochemical signals via a process called mechanotransduction. Colorectal cancer cells lie on the inside of the colon, which itself is constantly moving to absorb nutrients from food, and expel waste. These mechanics are called peristalsis. We do not have a good understanding of how peristalsis specifically alters cancer progression. In order to tackle this problem, we designed a new peristalsis bioreactor combining finite element modeling with rapid prototyping. Biological validation demonstrated that cells changed gene and protein expression uniquely in response to complex mechanics like peristalsis. This is impactful in colorectal cancer, where tumors experience peristalsis near-constantly. Our work will inform how peristalsis can be modulated (via meal patterns, intermittent fasting, and diet) to control colorectal cancer incidence, spread, and immune evasion.
Using regenerative immune engineering to find new therapeutics for Gulf War Illness
Gulf War Illness is a disorder that combat veterans from the Persian Gulf War 1 suffer from. It is thought to arise from toxic exposures during combat, and persists even 20-25 years after the war ended. Gulf War veterans suffer from many symptoms, including chronic diarrhea and constipation resulting from disrupted physiology of the colon. Our work uncovered the role of macrophages, a population of immune cells, in promoting Gulf War Illness. Immune cells like macrophages fan the fires of inflammation, resulting in disease amplification. We employ regenerative engineering and physiology to study how macrophages talk to other cells in the colon, like nerves and smooth muscle. We hope to find new therapeutics to improve the quality of life of Gulf War veterans.
How do cancer cells use nerves to spread?
Nerves are unique metastatic microenvironments for several cancers. The colorectal environment is densely innervated by the enteric nervous system (which is responsible for intestinal motility). Previously, nerves were thought to be passive modes for metastatic transmission, but more recent research has suggested that colorectal tumors may actively recruit enteric nerves that in turn provide trophic cues, allowing the tumor to grow and propagate. Within this project, we will utilize tissue engineering principles to create the enteric neuronal network that would typically innervate colorectal tumors using neural stem cells. By combining colorectal tumor micro-tissues and engineered nerve plexuses, we can study the peri-neural invasion metastatic phenomenon.