Project Details
Description
Abstract
Interactions between cancer cells and their microenvironment can facilitate tumor growth and progression by
altering gene expression and modulating tumor cell behavior such as by enhancing growth, survival, spread or
neovascularization. The transfer of bioactive molecules from one cell to another is a mechanism by which
tumor cells interact with other cells within their microenvironment. Non-coding (nc) RNA molecules are
capable of effecting genomic changes and can modulate gene expression. Thus, intercellular transfer of
ncRNA provides a powerful mechanism by which tumor cells can epigenetically modify their environment. The
overall objective of this proposal is to understand the molecular mechanisms by which ncRNA are released
within extracellular vesicles and their involvement in tumor cell-stromal cell interactions. The studies described
are based on our observations of highly selective release of some ncRNA within extracellular vesicles from
hepatocellular cancer (HCC) cells and their contribution to activation of cell signaling pathways in recipient
cells. Using human HCC or myofibroblastic cell lines, patient-derived HCC, and primary human hepatic stellate
cells, we will characterize vesicles and ncRNA that are functionally involved in inter-cellular RNA signaling.
These studies will (a) identify extracellular vesicle ncRNA mediators of tumor-stromal interactions and their
functional contribution to tumor growth, (b) define identifying characteristics of ncRNA-carrying vesicles and (c)
evaluate ESCRT-II dependent mechanisms by which ncRNA are sorted for release within vesicles during
tumor-stromal interactions. Using new approaches for the detection of RNA gene expression and inter-cellular
transfer with in-vitro and in-vivo tumor-stromal cell co-culture models, these studies will define the mechanistic
relationship between regulated release of extracellular vesicles, functional non-coding RNA and tumor cell-
stromal cell interactions. Elucidating the essential contribution of inter-cellular RNA signaling to tumor growth
will provide the basis for therapeutic strategies to target these interactions and mechanisms for the treatment
or prevention of HCC.
Status | Finished |
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Effective start/end date | 2/8/18 → 1/31/24 |
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