Treating KRAS-mutant lung adenocarcinoma (LUAD) remains
a major challenge in cancer treatment given the difficulties associated with
directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define
frequently co-occurring mutations with KRAS, which themselves
may lead to therapeutic vulnerabilities in tumors. Approximately 20% of
KRAS-mutant LUAD tumors carry loss-of-function (LOF)
mutations in Kelch-like ECH-associated protein 1
(KEAP1)2-4, a negative
regulator of nuclear factor erythroid 2-like 2 (NFE2L2;
hereafter NRF2), which is the master transcriptional regulator
of the endogenous antioxidant response5-10. The high
frequency of mutations in KEAP1 suggests an important role for
the oxidative stress response in lung tumorigenesis. Using a CRISPR/Cas9-based
approach in a mouse model of Kras-driven LUAD we examined the effects of
Keap1 loss in lung cancer progression. We show that loss of
Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD.
Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we show
that Keap1/Nrf2-mutant cancers are dependent on increased
glutaminolysis, and this property can be therapeutically exploited through the
pharmacological inhibition of glutaminase. Finally, we provide a rationale for
sub-stratification of human lung cancer patients with
KRAS-KEAP1 or
-NRF2-mutant tumors as likely to respond to glutaminase
inhibition.
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc- antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.
Despite mounting evidence for SARS-CoV-2 engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, ACE2. Here, using a myeloid-cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA-sequencing analysis of pulmonary cells from COVID-19 patients indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptors-mediated proinflammatory responses. Our findings suggest SARS-CoV-2-myeloid receptor interactions promote immune hyper-activation, which represents potential targets for COVID-19 therapy.
Highlights d Keap1 mutations drive non-essential amino acid (NEAA) dependency in cancer d Intracellular glutamate levels dictate cellular ability to survive NEAA deprivation d Restriction of NEAA can suppress Keap1 mutant tumor growth in vivo d Limiting glutamate by glutaminase inhibition enhances response to NEAA deprivation
Human pesticide exposure can occur both occupationally and
environmentally during manufacture and after the application of indoor and
outdoor pesticides, as well as through consumption via residues in food and
water. There is evidence from experimental studies that numerous pesticides,
either in isolation or in combination, act as endocrine disruptors,
neurodevelopmental toxicants, immunotoxicants, and carcinogens. We reviewed the
international literature on this subject for the years between 1990 and 2017.
The studies were considered in this review through MEDLINE and WHO resources.
Out of the n = 1817 studies identified,
n = 94 were reviewed because they fulfilled
criteria of validity and addressed associations of interest. Epidemiological
studies have provided limited evidence linking pre- and post-natal exposure to
pesticides with cancers in childhood, neurological deficits, fetal death,
intrauterine growth restriction, preterm birth, and congenital abnormalities
(CAs). In this review, the potential association between pesticide exposure and
the appearance of some human CAs (including among others musculoskeletal
abnormalities; neural tube defects; urogenital and cardiovascular abnormalities)
was investigated. A trend towards a positive association between environmental
or occupational exposure to some pesticides and some CAs was detected, but this
association remains to be substantiated. Main limitations of the review include
inadequate exposure assessment and limited sample size. Adequately powered
studies with precise exposure assessments such as biomonitoring, are warranted
to clarify with certainty the potential association between pesticide exposure
and human CAs.
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by x c -antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.
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