In the 1920s, Otto Warburg identified the first molecular feature of cancer: altered metabolism in the form of increased fermentation of glucose to lactate. This glucose-avidity of cancer underlies its modern diagnosis using FDG-PET imaging. Subsequent research identified enhanced nucleotide synthesis as another defining feature of cancer, leading to the development of the first class of targeted chemotherapeutics, antifolates. One of these, pemetrexed, discovered at Princeton by late Professor Edward Taylor, remains a first line therapy for lung cancer.
Building on the successes, the Ludwig Princeton Branch will investigate the fundamentals of metabolism, and how these go awry in cancer. Building on the strength of Princeton in the physical sciences and computation, we will innovate new methods for measuring and manipulating metabolism. We will explore the role of metabolism in cancer initiation, with obesity a major risk factor for endometrial, esophageal, liver, kidney, and pancreatic cancer. We will measure metabolic activity during tumorigenesis, from pre-malignant lesions to metastasis, in both tumors and their hosts, and between different cell types in the tumor microenvironment. The resulting knowledge will be used to develop new treatment regimens that manipulate metabolism to suppress tumor growth and augment antitumor immune response.
Related Publications
Yang Y, White E. Autophagy. 2023 Feb;19(2):726-728. doi: 10.1080/15548627.2022.2090694. Epub 2022 Jul 6.PMID: 35708538
Macroautophagy/autophagy defects are a risk factor for inflamatory bowel disease (IBD), but the mechanism remains unclear. We previously demonstrated that conditional whole-body deletion of the essential Atg7 (autophagy related 7) gene in adult mice (atg7Δ/Δ) causes specific tissue damage and shortens lifespan to three months primarily due to neurodegeneration with surprisingly no disturbing effects on the intestine. In contrast, we recently found that conditional whole-body deletion of other essential autophagy genes, Atg5 or Rb1cc1/Fip200 (atg5Δ/Δ or rb1cc1Δ/Δ), cause death within five days due to rapid inhibition of autophagy, elimination of intestinal stem cells, and loss of barrier function in the ileum. atg5Δ/Δ mice lose PDGFRA/PDGFRα+ mesenchymal cells (PMCs) and WNT signaling essential for stem cell renewal. Depletion of aspartate and nucleotides in atg5Δ/Δ ileum was revealed by novel mass-spectrometry imaging (MALDI-MSI), consistent with metabolic insufficiency underlying PMCs loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss because gradual whole-body atg5 deletion extends lifespan, phenocopying deletion of Atg7 or Atg12. Therefore, we established that autophagy is required for ileum PMC metabolism, stem cell maintenance and mammalian survival. PMC loss caused by autophagy deficiency may therefore contribute to IBD.
Bhatt V, Lan T, Wang W, Kong J, Lopes EC, Wang J, Khayati K, Raju A, Rangel M, Lopez E, Hu ZS, Luo X, Su X, Malhotra J, Hu W, Pine SR, White E, Guo JY.Cell Death Dis. 2023 Jan 26;14(1):61. doi: 10.1038/s41419-023-05592-8.PMID: 36702816
LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.
Ferrer M, Mourikis N, Davidson EE, Kleeman SO, Zaccaria M, Habel J, Rubino R, Flint TR, Connell CM, Lukey M, White EP, Coll AP, Venkitaraman AR, Janowitz T. bioRxiv. 2023 Feb 18:2023.02.17.528937. doi: 10.1101/2023.02.17.528937. Preprint. PMID: 36824830
Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.