Mechanisms for environmental microplastics-enhanced colorectal tumor progression - Project Summary In response to the Notice of Special Interest (NOSI) NOT-ES-23-002, our research addresses the urgent concern of escalating plastic pollution. Despite numerous reports indicating the ubiquitous presence of plastics in the environment and growing global concern for ecosystems and human health, plastic production and use continue to grow unabatedly. Humans are exposed to plastic particles mainly through ingestion of contaminated food or water, through inhalation, or through skin contact. Humans consume up to 5g (weight of a credit card) microplastics weekly, and colonic epithelial cells will face the brunt of this toxic exposure. Recent studies provide evidence for the accumulation of microplastics in multiple human organs including the colon. Toxic exposure to microplastics has been linked to the disruption of colonic epithelial cell structure and function. Moreover, studies in different preclinical models including mice indicate that microplastics exposure leads to various adverse intestinal effects including inflammation, barrier dysfunction, and microbial imbalance. Long-standing intestinal inflammation and oxidative stress increase the risk of colorectal cancer (CRC) development. However, to date, there have been no studies investigating the influence of microplastics on colon tumor growth and metastasis in vivo. Thus, investigation into the potential association between the environmental microplastics exposure and the risk of CRC is merited. Our objective is to unveil the molecular mechanisms linking microplastics exposure to CRC. We hypothesize that microplastics trigger PIEZO1- dependent oxidative stress and hypoxia inducible factor (HIF)-3α signaling, promoting CRC progression. Our hypothesis is based on our data showing that different microplastics consistently and dramatically promote oxidative stress in a mechanosensing ion channel PIEZO1 dependent manner. Moreover, microplastics activate HIF-3α signaling, which drives growth, migration, and metastasis of colon tumors in preclinical models. The proposal highlights the unique PIEZO1 trigger (Aim 1) and the immediate downstream HIF-3α signaling (Aim 2) of oxidative stress, integrating human relevance through archived colon tissues from New Mexico's diverse and underprivileged population, as well as human colonoids (both normal and tumor, Aim 3). These goals aim to enhance our comprehension of the fundamental mechanisms underlying microplastics' toxicity and identify actionable elements for community-level disease prevention and treatment.
