Date of Award

8-11-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Zhi-Ren Liu

Second Advisor

Ritu Aneja

Third Advisor

Charlie Garnett Benson

Abstract

Fibrosis represents a pathological condition characterized by excessive deposition of the extracellular matrix. Myofibroblasts are the primary source of extracellular matrix in fibrosis. Their resistance to turnover and elevated collagen synthetic capacity play critical roles during organ fibrosis progression, mechanisms of which are not fully understood. Here we report that high levels of extracellular PKM2 are detected in lung fibrosis patient tissues. The extracellular PKM2 promotes lung fibrosis by protecting myofibroblasts from apoptosis and increasing collagen production in myofibroblasts. Further, our results show that the extracellular PKM2 interacts with integrin αvβ3 and activates integrin αvβ3-FAK-PI3K signaling axis in myofibroblasts. Moreover, neutralization of PKM2 with the antibody is effective in attenuating lung fibrosis. Fibrosis is a hallmark of cancer. Fibrosis in cancer results from the increased deposition of a cross-linked collagen matrix by myofibroblasts. Fibrosis in cancer has been shown to enhance cancer growth and metastasis. High levels of PKM2 are identified in the blood circulation of cancer patients of many types. However, the effects of extracellular PKM2 on fibrosis in cancer has not been well studied. Here we show that the extracellular PKM2 promotes lung metastasis in breast cancer and neutralization of PKM2 with antibody reduces tumor burden and lung metastasis. These effects are accompanied by marked changes in collagen content and myofibroblast population. In summary, extracellular PKM2 facilitates the lung fibrosis by enhancing survival and collagen production of myofibroblasts via integrin αvβ3-FAK-PI3K signaling axis. In addition, extracellular PKM2 increases fibrosis level in breast cancer which favors cancer growth and metastasis. Our study suggests a new therapeutic target for the treatment of fibrosis-related diseases.

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