ABSTRACT
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
Subject(s)
Chemokine CXCL5 , DNA-Binding Proteins , Dioxygenases , Lung Neoplasms , Neutrophils , Proto-Oncogene Proteins , STAT3 Transcription Factor , Animals , Neutrophils/metabolism , STAT3 Transcription Factor/metabolism , Mice , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Chemokine CXCL5/metabolism , Chemokine CXCL5/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Humans , Dioxygenases/metabolism , Pinocytosis , Cell Line, Tumor , Neutrophil Infiltration , Mice, Knockout , Mice, Inbred C57BL , Lipid MetabolismABSTRACT
Value-based decision making involves choosing from multiple options with different values. Despite extensive studies on value representation in various brain regions, the neural mechanism for how multiple value options are converted to motor actions remains unclear. To study this, we developed a multi-value foraging task with varying menu of items in non-human primates using eye movements that dissociates value and choice, and conducted electrophysiological recording in the midbrain superior colliculus (SC). SC neurons encoded "absolute" value, independent of available options, during late fixation. In addition, SC neurons also represent value threshold, modulated by available options, different from conventional motor threshold. Electrical stimulation of SC neurons biased choices in a manner predicted by the difference between the value representation and the value threshold. These results reveal a neural mechanism directly transforming absolute values to categorical choices within SC, supporting highly efficient value-based decision making critical for real-world economic behaviors.
Subject(s)
Choice Behavior/physiology , Reward , Superior Colliculi/physiology , Animals , Electric Stimulation/instrumentation , Eye Movement Measurements , Macaca mulatta , Male , Microelectrodes , Models, Animal , Neurons/physiology , Photic Stimulation , Saccades/physiology , Single-Cell Analysis , Superior Colliculi/cytologyABSTRACT
Microsaccades are small-amplitude (typically <1°), ballistic eye movements that occur when attempting to fixate gaze. Initially thought to be generated randomly, it has recently been established that microsaccades are influenced by sensory stimuli, attentional processes, and certain cognitive states. Whether decision processes influence microsaccades, however, is unknown. Here, we adapted two classic economic tasks to examine whether microsaccades reflect evolving saccade decisions. Volitional saccade choices of monkey and human subjects provided a measure of the subjective value of targets. Importantly, analyses occurred during a period of complete darkness to minimize the known influence of sensory and attentional processes on microsaccades. As the time of saccadic choice approached, microsaccade direction became the following: 1) biased toward targets as a function of their subjective value and 2) predictive of upcoming, voluntary choice. Our results indicate that microsaccade direction is influenced by and is a reliable tell of evolving saccade decisions. Our results are consistent with dynamic decision processes within the midbrain superior colliculus; that is, microsaccade direction is influenced by the transition of activity toward caudal saccade regions associated with high saccade value and/or future saccade choice.
