Chemotherapy and radiation are still standard therapies for many cancers and can be very effective in some contexts to block cancer cell growth. These types of acute treatments generate massive DNA damage in exposed tissues which causes cell death and also generates senescence - a state of permanent arrest. Unfortunately, senesence does not just block cancer cell growth but can also induce reprogramming of cellular signaling and metabolism, called the senescence-associated secretory pathway (SASP), that induces inflammation in surrounding tissues. This inflammatory response actually stimulates the growth of neighboring cells and has been shown to promote secondary tumor progression in some m...

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Chemotherapy and radiation are still standard therapies for many cancers and can be very effective in some contexts to block cancer cell growth. These types of acute treatments generate massive DNA damage in exposed tissues which causes cell death and also generates senescence - a state of permanent arrest. Unfortunately, senesence does not just block cancer cell growth but can also induce reprogramming of cellular signaling and metabolism, called the senescence-associated secretory pathway (SASP), that induces inflammation in surrounding tissues. This inflammatory response actually stimulates the growth of neighboring cells and has been shown to promote secondary tumor progression in some model systems.

In this proposal we are investigating the mechanisms that underlie both the cell arrest that occurs during senescence as well as the inflammatory SASP response that is ultimately tumor-promoting. The protein kinase ATM is a key signaling enzyme that regulates both of these responses, but preliminary data suggests that the SASP response is specifically activated by a redox-sensitive pathway. Here we test the hypothesis that oxidative activation of ATM is critical for the SASP and for the communication of inflammation to neighboring cells. We also will determine if an oxidation-specific binding partner of ATM is essential for this process, which would generate an attractive target to block senescence-induced inflammation in human cancers.

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