Breast cancer-secreted microRNAs in the pre-metastatic niche
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: Metastasis, the spread of cancer to distant organs from the original tumor site, is the most advanced stage and leading cause of death in breast cancer (BC). Patients with metastatic BC (MBC) have a median survival of only 1–2 years, and lack efficient treatment options. Therefore, there is urgent need for early diagnosis or reliable prediction of metastasis, and for novel therapies that target early steps involved in cancer spread in order to prevent metastasis.
 
 
 
 
 
 Recently discovered small RNA molecules, called micrRNAs (miRNAs), will be investigated in this study for their role in these diagnostic and therapeutic applications. We will identify cancer secreted miRNAs whose levels in blood are linked to metastasis in BC patients. These miRNAs are valid candidates for blood-based biomarkers that can predict BC metastasis at a nonmetastatic stage. Because BC-secreted, metastasis-related miRNAs can travel to other organs through the blood, they may invade and alter the environment (pre-metastatic niche) in a distant healthy organ to make it favorable for the growth of BC cells, thereby enabling BC metastases to form in that organ. Therefore, blocking this function of BC-secreted, metastasis-related miRNAs may protect the distant organ and prevent metastasis of BC.
 
 
 
 
 
 First, we will identify BC-secreted miRNAs associated with metastasis. Using an Ultra High Throughput Sequencing System (Solexa), we will compare the miRNAs secreted by BC cells with high and low/no metastatic potential, and will compare the blood miRNA pattern among BC patients who developed metastases after an initial, non-metastatic BC diagnosis and those who did not within a similar follow-up time. Metastasis-associated miRNAs identified in this aim may include both early diagnostic markers and therapeutic targets for MBC. Next, we will determine the function of BC-secreted, metastasis-associated miRNAs in the pre-metastatic niche. The biological functions and mechanisms of BC-secreted miRNAs will be investigated by a combination of computational tools and molecular biological approaches, such as the use of inhibitors and mimics of miRNAs. These functional studies will be carried out in various types of niche cells, including those important for new blood vessel formation, secretion of factors that encourage the growth of cancer cells, and immuno-modulation (such as inflammation). In addition, a mouse model will be used to directly examine the effects of these miRNAs on metastasis.
 
 
 
 
 
 This study will provide proof-of-principle for predicting the risk of BC metastasis based on the miRNA profile of the patient’s blood. Identification of blood-based miRNAs associated with metastasis, as an immediate outcome of this study, will enhance our ability to target lethal metastasis at an earlier stage and reduce the incidence of metastasis and mortality. The study will also reveal novel therapeutic targets that may be pharmaceutically targeted in BC treatments to protect organs that are common metastatic sites from actions of cancer-secreted miRNAs and therefore, to prevent metastasis, increase survival and improve quality of life of BC patients.