Metabolic scavenging by cancer cells: when the going gets tough, the tough keep eating

Cancer is fundamentally a disease of uncontrolled cell proliferation. Tumour metabolism has emerged as an exciting new discipline studying how cancer cells obtain the necessary energy and cellular ‘building blocks’ to sustain growth. Glucose and glutamine have long been regarded as the key nutrients fuelling tumour growth. However, the inhospitable tumour microenvironment of certain cancers, like pancreatic cancer, causes the supply of these nutrients to be chronically insufficient for the demands of proliferating cancer cells. Recent work has shown that cancer cells are able to overcome this nutrient insufficiency by scavenging alternative substrates, particularly proteins and lipids. Here, we review recent work identifying the endocytic process of macropinocytosis and subsequent lysosomal processing as an important substrate-acquisition route. In addition, we discuss the impact of hypoxia on fatty acid metabolism and the relevance of exogenous lipids for supporting tumour growth as well as the routes by which tumour cells can access these lipids. Together, these cancer-specific scavenging pathways provide a promising opportunity for therapeutic intervention

Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation

Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids

Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition

Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach

Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth

The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphological changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has anti-tumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries

The case of the purloined child : detective fiction and criticism

This thesis examines ideas of the child in detective fiction in both adult and children's literature criticism drawing mainly on the theoretical work of Jacqueline Rose in The Case of Peter Pan Or the Impossibility of Children's Fiction (1984) as well as on the work of Jacques Derrida included in The Purloined Poe: Loean, Derrida and Psychoanalytic Reading (eds. Muller and Richardson, 1989). Rose argues that the child is a construction rather than having a reality which is then brought into the text to stabilise and secure meaning in language. Derrida argues that the application of the truth of psychoanalysis (that Lacan claims to have found in The Purloined Letter') limits the play of written word and stabilises and fixes meaning in language. Both critics argue for a reading that reads implications rather than a reading that applies some pre-discursive truth which is either the child or psychoanalysis. The thesis focuses its questioning of essentialist assumptions about childhood and reading through a close focus on children's detective fiction criticism, including Gavin, Adrienne E. and Christopher Routledge edited volume Mystery in Children's Literature: From the Rational to the Supernatural (2001); and the Special Issue of Children's Literature Association Quarterly (Vol: 10,2010) at the 25th anniversary of the publication of Jacqueline Rose's The Case of Peter Pan. A questioning of wider essentialist assumptions about reading and detective fiction basing its case on The Yellow Face' is pursued through a close analysis of Arthur Conan Doyle's Sherlock Holmes story The Yellow Face' and its criticism, including Henry Cuningham's 'Sherlock.Holmes and the case of race', Jinny Huh's 'Whispers of Norbury: Sir Arthur Conan Doyle and the Modernist Crisis of Racial (Un)Detection', and Thomas L. Stix's 'The Yellow Face'. Through these close analyses the thesis argues that childhood, detective fiction, and 'popular' fiction more widely are usually assumed as '(un)readable' in relying on a simple reality and language which does not need to be interpreted, but is, as Rose argues, seen as transparently accessible. The thesis traces the implication of such assumptions in the criticism offering readings of what is invested in such claims, as well as demonstrating how we might read, as Felman puts it, otherwise.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Regulation of macropinocytosis in pancreatic cancer and implications on drug effectiveness

No abstract available

Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation