Terrestrial organisms have evolved mechanisms to anticipate the environmental changes associated with diurnal variations in the environment. The primary such mechanism is the circadian timer which is a molecular clock present in every cell of mammals. In order to adjust to external variations, the circadian clock is plastic and responds to environmental stimuli. Two such stimuli are light and food timing. In this dissertation I describe two separate studies, one in mice and another in humans where we have attempted to characterize these two stimuli. In chapter 2, I describe a series of experiments performed in mice in which we have defined the extent of circadian and light driven transcription in the master clock, namely the suprachiasmatic nucleus, residing in the hypothalamic region of the brain. In chapter 3, I describe the development of a behavioral monitoring and data analysis system for understanding the extent of temporal spread of caloric intake in people. To our knowledge this is the first time that smartphones have been employed to characterize human behavior. Our data reveals previously unknown aspects of eating behaviors. In chapter 4, the results obtained from the human behavioral study are discussed. Lastly, in chapter 5, I mention our strategy for future studies using the approach described in chapter 3 and 4. Overall, this dissertation expands our knowledge of light and feeding time inputs to the mammalian timekeeping mechanisms

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.