Research | Lyssiotis Lab

Pancreatic cancer is the deadliest major cancer. This is attributed in part to the profound resistance to all available therapies. A hallmark of pancreatic tumors, and one that contributes to this resistance, is the metabolic environments that they create (Halbrook and Lyssiotis, Cancer Cell 2017). Based on this concept, my lab has been mapping the metabolic pathways in pancreatic cancer to identify aspects of metabolism that are unique or highly over-utilized in an effort to find new inroads to treat this disease. These efforts have led to four paradigm-shifting findings. I demonstrated that pancreatic tumors are oncogene-addicted to mutant Kras and that a principal role of Kras in this context is to maintain glucose (Ying et al. Cell 2012) and glutamine metabolic pathways (Son et al. Nature 2013). I have also revealed that pancreatic cancer cells in a tumor are metabolically heterogeneous, with a large proportion of the cancer cells being dependent on Kras-mediated glucose and glutamine metabolism, as above. In contrast, the sub-fraction of cells that are responsible for disease relapse rely on mitochondrial metabolism (Viale et al. Nature 2014). More recently, we demonstrated that pancreatic cancers depend on exogenous cysteine to safeguard against ferroptosis, and that cysteine deprivation represents an exploitable therapeutic vulnerability (Badgley et al. Science 2020). Most relevant to this application, we mapped the spectrum of nutrients utilized by pancreatic cancer cells and defined uridine metabolism through UPP1 as a novel, exploitable vulnerability (Nwosu et al. Nature 2023). I served as lead/co-lead or senior investigator for these studies.

A consequence of deregulating nutrient uptake and rewiring metabolic pathways is that cancer cells become uniquely dependent on, and vulnerable to, disruption of pathways and processes that healthy cells can live without. Using a variety of biochemical and analytical techniques, my research has revealed how several of such processes are rewired in cancer and have begun to use this knowledge to design targeted therapies that exploit these metabolic dependencies. For example, I described a novel pathway by which the amino acid glutamine is metabolized in pancreatic cancer cells. Notably, the activity of this pathway is required to maintain redox balance and proliferation in these cells, where inhibition is profoundly growth inhibitory (Son et al. Nature 2013). We have five patents in this space and preclinical small molecule inhibitor programs for multiple targets in the pathway (Yoshida et al. Biochemistry 2022; Kerk et al. eLife 2022; Kremer et al. Nat Comm 2021; Nelson et al. Can & Met 2020). I served as senior investigator in these studies.

Tumors are dynamic pseudo-organs that contain numerous cell types interacting to create a unique physiology. To support (i) tumor growth, (ii) immune evasion, and (iii) therapeutic resistance, our group has demonstrated that the various cell types in tumors engage in metabolic communication (Kerk et al. Nature Rev Can 2021). (i) We discovered that the malignant cells cooperatively share nutrients with surrounding non-cancerous cells to support tumor growth (Sousa et al. Nature 2016; Kim et al. eLife 2021). (ii) We found that malignant cells competitively capture and deprive cytotoxic T cells of methionine (Bian et al. Nature 2020) and arginine (Menjivar et al. eLife 2023) to impair anti-tumor immunity. (iii) We also described roles promoting therapeutic resistance for microenvironmental asparagine (Halbrook et al. Nat Cancer 2022), tumor associated macrophage-derived deoxycytidine (Halbrook et al. Cell Met 2019), and regulatory T cell-derived adenosine (Maj et al. Nat Immunol 2017). References are listed either in the “Recent Publications” section above or below. My laboratory led or co-led these studies, and I served as a senior investigator.

Alongside the advancements metabolism detailed above, my research lab has been actively developing new techniques, methods, and technologies to study these processes. Principally, we employ mass spectrometry (MS)-based metabolomics. We recently published our studies integrating data sets across a range of sample types, where we describe metabolome-wide changes conserved across species and sample types reflecting inherent biological programs (Lee et al. Metabolomics 2019). Similarly, we have developed numerous protocols to analyze these datasets (Oruganty et al. Can & Met 2020) and to trace metabolism using stable isotope-labeled substrates (e.g. glucose, amino acids, lipids) (Yuan et al. Nat Prot 2019). Most recently, we described a method to integrate imaging of mitochondrial parameters alongside the seahorse metabolic flux assay that enables a more detailed characterization of bioenergetic programs (Little et al. Comm Biology 2020). I served as senior investigator in these studies.