Systemic metabolic reprogramming by BC-secreted microRNAs

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Shizhen Emily Wang, Ph.D. - Shizhen Emily Wang, Ph.D. -
Award Cycle: 2014 (Cycle 20) Grant #: 20IB-0118 Award: $180,515
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

This is a collaboration with: 20IB-0118A -

Initial Award Abstract (2014)

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.




Progress Report 1 (2015)

The goal of this study is to determine how breast cancer (BC)-secreted microRNAs (miRNAs) alter nutrient metabolism in normal non-cancerous cells, and the effect of this mechanism on BC metastasis. Reprogrammed energy metabolism to fuel rapid cell proliferation in an emerging hallmark of cancer. Through various mechanisms, cancer cells often exhibit enhanced ability to metabolize nutrients such as glucose and amino acids. On the other hand, a competition of nutrients exists between cancer cells and normal cells co-residing in the same tumor microenvironments. In this project, we propose to focus on the novel crosstalk between BC cells and non-cancerous cells that lead to suppressed nutrient metabolism by the latter and therefore facilitate nutrient utilization by cancer cells. Specifically, we will focus on BC-secreted miRNAs for their role in regulating normal 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. 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.

In Year 1, we have successfully completed about 75% of the proposed studies by investigating the function of miR-122, a BC-secreted miRNA, in suppressing glucose metabolism in normal cells. This work led to a recent publication in Nature Cell Biology. We show that cancer cells can suppress glucose uptake by non-cancerous cells in the pre-metastatic niche, by secreting vesicles that carry high levels of miR-122. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells through downregulating a glycolytic enzyme called pyruvate kinase. Inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

In the remaining funding period, we will further investigate the function of additional BC-secreted miRNAs, using methods similar to our miR-122 study and as we originally proposed for this project. 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. 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 spread.




Progress Report 2 (2015)

During the funding period, we have successfully completed most of the proposed studies by investigating the function of miR-122, a BC-secreted miRNA, in suppressing glucose metabolism in normal cells. This work led to a recent publication in Nature Cell Biology. We show that cancer cells can suppress glucose uptake by non-cancerous cells in the pre-metastatic niche, by secreting vesicles that carry high levels of miR-122. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell derived miR-122 suppresses glucose uptake by niche cells through downregulating a glycolytic enzyme called pyruvate kinase. Inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

During the no-cost extension, we will further investigate the function of additional BC-secreted miRNAs, using methods similar to our miR-122 study and as we originally proposed for this project. 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. 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 spread.

Publications:
Cross-kingdom inhibition of breast cancer growth by plant miR159
Cancer-derived extracellular vesicles: the ‘soil conditioner’ in breast cancer metastasis?



Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis.
Periodical:Nature Cell Biology
Index Medicus: Nat Cell Biol
Authors: Fong MY, Zhou W, Liu L, et al.
Yr: 2015 Vol: 17 Nbr: 2 Abs: Pg:183-194

Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications DOI: 10.1158/1078-0432.CCR-16-0028
Periodical:Clinical Cancer Research
Index Medicus: Clin Cancer Res
Authors: Andrew R. Chin, Shizhen Emily Wang
Yr: 2016 Vol: Nbr: Abs: Pg: