Graduation Date

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Jing Jenny Wang

Abstract

Metastasis is the major cause of death in colorectal cancer patients, mainly due to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of colorectal cancer metastasis is, therefore, essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies to prevent or target metastasis. LGR5 is leucine-rich repeat containing G protein-coupled receptor (GPCR) and was discovered as a marker for proliferating adult stem cells in the small intestine. LGR5 and its homologs LGR4 and LGR6 are receptors of R-spondins (RSPOs), which are secreted agonists of canonical Wnt signaling. Upon binding RSPOs, they form a physical complex with Wnt receptor Frizzled and its co-receptor LRP6 to regulate Wnt canonical signaling. Here we show that RSPO-LGR5 activates TGFβ signaling in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuates TGFβ signaling, increases cell proliferation, survival and metastasis. Mechanistically, with the presence of RSPOs, LGR5 forms and enhances complex formation with TGFβ receptors to activate downstream signaling. Our study underlies a novel crosstalk between Wnt and TGFβ signaling in colon cancer cells. Since TGFβ signaling is defective in most late-stage colon cancer and its restoration has been shown to suppress colon cancer tumorigenicity, our findings would provide an alternative mechanism to activate TGFβ signaling and suppresses colon cancer tumorigenicity and metastasis

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