Project Grant F31DE034302

THERAPY INDUCED SENESCENCE AS A POTENT THERAPEUTIC TARGET - PROJECT SUMMARY/ABSTRACT HEAD AND NECK CANCER IS THE SIXTH MOST PREVALENT CANCER WORLDWIDE, WITH 90% OF CASES DIAGNOSED AS HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). THOUGH INITIAL TREATMENTS WITH DNA DAMAGING AGENTS SUCH AS RADIATION AND CISPLATIN ARE EFFECTIVE IN LIMITING TUMOR PROGRESSION, 50% OF HNSCC PATIENTS WILL EXPERIENCE TUMOR RELAPSE. THERAPY-INDUCED SENESCENCE (TIS), A DORMANT YET METABOLICALLY ACTIVE CELLULAR STATE, MAY BE A CONTRIBUTING FACTOR TO TUMOR CELL PROLIFERATIVE RECOVERY. TIS IS CHARACTERIZED BY MORPHOLOGICAL AND ENZYMATIC CHANGES AS WELL AS THE RELEASE OF SECRETORY PROTEINS COLLECTIVELY CALLED "SASP" (SENESCENCE ASSOCIATED SECRETORY PHENOTYPE). THIS INCLUDES THE RELEASE OF CYTOKINES, CHEMOKINES, GROWTH FACTORS AND OTHER PROTEINS THAT IMPACT PARACRINE AND AUTOCRINE SIGNALING. THE CGAS-STING (CYTOSOLIC GMP-AMP SYNTHASE STIMULATOR OF INTERFERON GENES) PATHWAY, A KEY COMPONENT OF THE INNATE IMMUNE RESPONSE, IS ACTIVATED WITH THE PRESENCE OF DAMAGED CYTOSOLIC DNA, ULTIMATELY PROMOTING THE EXPRESSION OF INTERFERON-ASSOCIATED GENES NECESSARY FOR THE RELEASE OF PROINFLAMMATORY CYTOKINES AND CHEMOKINES, INCLUDING A VARIETY OF SASP PROTEINS. THUS, THE CGAS-STING PATHWAY MAY BE AN IMPORTANT UNDERLYING MECHANISM IN THE REGULATION OF TIS. OUR PRELIMINARY DATA DEMONSTRATED THAT STING EXPRESSING HNSCC CELLS RECOVERED PROLIFERATION APPROXIMATELY 12 DAYS FOLLOWING SENESCENCE INDUCTION BY CISPLATIN WHILE STING KNOCKOUT CELLS REMAINED GROWTH-ARRESTED. THIS FINDING GENERATED THE HYPOTHESIS THAT CGAS-STING MAY BE NECESSARY FOR PROLIFERATIVE RECOVERY VIA THE SECRETION OF SIGNALING PROTEINS. RNASEQ AND PROTEOMIC MASS SPECTROSCOPY OF STING WILDTYPE AND KNOCKOUT CELLS TREATED WITH CISPLATIN TO INDUCE SENESCENCE REVEALED MULTIPLE GROWTH FACTOR AND CYTOKINE CANDIDATES. QRT-PCR IDENTIFIED THAT LEUKEMIA INHIBITORY FACTOR (LIF) WAS INDUCED BY CISPLATIN AND WAS DOWNREGULATED WITH STING SUPPRESSION. A MEMBER OF THE IL-6 FAMILY, LIF HAS BEEN FOUND TO CONTRIBUTE TO TUMORIGENESIS, TUMOR CELL INVASION, AND MIGRATION IN STUDIES OF ORAL SQUAMOUS CELL CARCINOMA, NASOPHARYNGEAL CARCINOMA, PANCREATIC DUCTAL ADENOCARCINOMA, AND OTHER SOLID TUMOR TYPES. ADDITIONALLY, LIF HAS BEEN EXPLORED AS A THERAPEUTIC TARGET VIA THE DEVELOPMENT OF SMALL-MOLECULE LIF INHIBITORS AND HUMANIZED MONOCLONAL ANTIBODIES. THUS, WE HYPOTHESIZE THAT CGAS-STING MAY FACILITATE PROLIFERATIVE RECOVERY VIA ITS REGULATION OF LIF. WE SEEK TO CHARACTERIZE THE IMPACT OF CGAS-STING ON PROLIFERATIVE RECOVERY VIA LIF BOTH IN VITRO AND IN VIVO AS WELL AS EVALUATE THE POTENTIAL OF LIF AS A THERAPEUTIC TARGET TO COMBAT TUMOR RELAPSE. PREVIOUS STUDIES OF CGAS-STING HAVE PREDOMINANTLY FOCUSED ON ITS ROLE IN THE INNATE IMMUNE RESPONSE; THUS OUR PROPOSED STUDIES WILL PROVIDE CRITICAL INVESTIGATION OF THE CELL AUTONOMOUS FUNCTIONS OF CGAS- STING AND LIF THAT MAY INFLUENCE THE OVERALL FUNCTION OF CGAS-STING IN THE TUMOR CELL RESPONSE TO CHEMOTHERAPY AND POTENTIALLY OTHER TREATMENT MODALITIES THAT PROMOTE SENESCENCE IN HEAD AND NECK CANCER.