REGULATION OF LIPID HOMEOSTASIS DURING LOW OXYGEN ADAPTATION IN SCHIZOSACCHAROMYCES POMBE

Adaptation to environmental change is a hallmark of life, and fundamental factors including oxygen, lipids, nutrients, pH, and temperature are in a constant state of flux in many cellular environments. All organisms, from single-celled yeast to multicellular humans, must sense and adapt to these changing environmental conditions in order to survive and reproduce. This sensing and response is often regulated on the level of transcription factors, so that a broad set of genes can be altered in concert through changes in a single or small number of sensors. Due to the essential nature of these adaptations, the relevant transcription factor pathways are often conserved across species and can be highly complex in order to precisely tune the response. Therefore, study of these transcription factor pathways in the non-pathogenic fungus Schizosaccharomyces pombe may establish universal paradigms that are broadly applicable to other fungal species or to eukaryotes in general. In this thesis, I defined a novel role for the AAA+ ATPase Cdc48 and its cofactor Ufd1 in the Golgi localization of the Dsc E3 ligase complex. This role ultimately impinges on cleavage of the SREBP transcription factor responsible for regulation of sterol biosynthesis in response to low oxygen in fission yeast. Through that work I also generated the first list of Cdc48 binding proteins in S. pombe, which can be used in the future to identify new Cdc48 cofactors and pathways that may be important to other cellular processes. I also uncovered a new regulator of the low oxygen response - Mga2. I demonstrated that Mga2 transcriptionally regulates phospholipid biosynthesis in response to low oxygen, acting alongside SREBPs to regulate lipid homeostasis. Further, I showed evidence of potential coordination of SREBP and Mga2 activation, suggesting broader co-regulation of these two pathways to keep overall lipid homeostasis in balance. In the future, I hope these insights will lead to establishment of Mga2 as important for low oxygen adaptation in pathogenic fungi

Epithelial-Mesenchymal Plasticity in Circulating Tumor Cells, the Precursors of Metastasis

Circulating tumor cells offer an unprecedented window into the metastatic cascade, and to some extent can be considered as intermediates in the process of metastasis. They exhibit dynamic oscillations in epithelial to mesenchymal plasticity and provide important opportunities for prognosis, therapy response monitoring, and targeting of metastatic disease. In this manuscript, we review the involvement of epithelial-mesenchymal plasticity in the early steps of metastasis and what we have learned about its contribution to genomic instability and genetic diversity, tumor progression and therapeutic responses using cell culture, mouse models and circulating tumor cells enriched from patients.</p

TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state

Summary: TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance