Systemic metabolic reprogramming by BC-secreted microRNAs
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: One emerging hallmark of cancer is the altered use of energy to fuel rapid growth of tumor. Using various mechanisms, cancer cells often have enhanced abilities to utilize nutrients such as glucose and amino acids. However, cancer cells compete for access to these nutrients with non-cancerous cells co-residing in the tumor microenvironments. In this project, we will focus on the novel crosstalk between breast cancer (BC) cells and non-cancerous cells that suppresses the use of nutrients by non-cancerous cells and thereby facilitates nutrient use by BC cells. Specifically, we will focus on defining the role of BC-secreted microRNAs (miRNAs) in regulating cell metabolism. MiRNAs are small RNA molecules that regulate gene expression. They can be detected in the blood, and are emerging biomarkers for human diseases and novel mediators of cell-to-cell communication. Using cell-secreted particles as vehicles, miRNAs secreted by cancer cells can travel to and enter various types of non-cancerous cells, and then affect the activity of these cells. We hypothesize that a set of BC-secreted miRNAs can alter nutrient metabolism in non-cancerous cells to create metabolic microenvironments that facilitate cancer growth and spread. 
 
 
 
 
 
 
 
 First, we will determine the effects of BC-secreted particles known as “exosomes” on nutrient metabolism in non-cancerous cells. Exosomes secreted by BC or non-cancerous cells will be used to treat various types of cells that are abundant in the tumor microenvironments, as well as to treat mice from which various tissues (mammary gland, lung, brain, liver, and serum) will be collected. Exosome-treated cells and tissues will be analyzed for levels of molecules reflecting nutrient metabolism and gene expression. Second, we will determine the role of BC-secreted miRNAs in altering the metabolism of non-cancerous cells and its link to cancer spread to distant organs (known as metastasis). Using a unique mouse model established in our preliminary studies, we will determine the effect of selected miRNAs on promoting BC metastasis. We will also use mouse models to evaluate the effects of anti-miRNA compounds as potential therapeutic agents for BC. 
 
 
 
 
 
 
 
 Understanding how BC-secreted miRNAs contribute to the co-evolution of the tumor-hosting environment, in particular, how non-cancerous cells are manipulated by cancer cells to favor cancer growth, will provide novel insights into the dynamic communication between cancer and the host during disease progression. This study will examine the novel concept that cancer cells, by secreting metabolism-regulating miRNAs, can reduce the use of nutrients by non¬cancerous cells, allowing cancer cells to more readily access nutrients and sustain their rapid growth. Novel miRNA-mediated pathways that contribute to this cancer-derived nutrient reallocation will be identified, which may reveal novel therapeutic targets that can be pharmaceutically targeted during early stages of BC to protect the niche cells from nutrient deprivation and prevent cancer progression and metastasis. In addition, this project may identify novel mechanistic links between BC and metabolic disorders, such as diabetes, which would open new avenues for studying BC co-morbidities.