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Hexokinase 2 Discerns a Novel Circulating Tumor Cell Population Associated With Poor Prognosis in Lung Cancer Patients

Scientists have developed a novel method to better detect the circulating tumor cells (CTCs) that are a telltale sign of metastases (PNAS 2021; Researchers looked at hexokinase 2, or HK2, a key enzyme in glucose metabolism. Conventional CTC detection methods, as exemplified by the FDA-cleared CellSearch system, normally rely on the use of a family of proteins called cytokeratins (CKs) typically found in epithelial tissues. As roughly 90 percent of human cancers arise in epithelial tissues and express CKs, these methods work well in many major cancer types. However, their performance in non-small cell lung cancer (NSCLC) is suboptimal, despite the highly aggressive nature of NSCLC, which represents a long-standing puzzle in this field. The researchers addressed this challenge to achieve a greater spectrum for CTC detection through exploiting a common feature of a wide range of cancer cells-elevated glucose consumption driven by the high level of HK2. The use of HK2 as a biomarker allowed them to develop metabolic activity-based methods for the identification of a novel CTC population without CK expression that was normally overlooked by conventional methods. This CK-negative CTC population was a prevalent subtype in 50 percent of NSCLC patients analyzed and was the only subtype in one-third of them, although all these patients were bearing CK-positive primary tumors, indicating that these tumor cells transitioned to CK-negative after detaching from the primary sites and shedding into the bloodstream in these NSCLC patients. Sequencing analysis revealed metastasis and drug-resistance molecular signatures associated with CK-negative CTCs. Consistently, patients with prevalent CK-negative CTCs in blood were having poorer therapy response, shorter progression-free survival, and a higher chance for metastasis. Interestingly, the researchers found that patients with the EGFR L858R mutation are more likely to have CK-negative CTCs circulating in their blood, which partially explains a long-standing clinical observation, namely the suboptimal therapeutic efficacy of first-line EGFR inhibitors in EGFR L858R-mutant tumors.



Survival Associations of Skeletal Muscle With Symptom Burden and Clinical Outcomes in Hospitalized Patients With Advanced Cancer

New research finds muscle mass (quantity) correlated with survival, while muscle radiodensity (quality) was associated with symptom burden, health care use, and survival in patients with advanced cancer undergoing an unplanned hospitalization (JNCCN 2021; The researchers also found nearly two-thirds of the patients in that population had significant sarcopenia, and that those with a higher body mass index tended to have lower muscle quality despite higher quantity. They highlight the need for additional work to continue investigating how best to utilize computerized tomography (CT) scans to measure muscle mass and density to improve clinical outcomes. The researchers evaluated muscle data from the CT scans of 677 patients with advanced cancer who had an unplanned hospitalization between September 2014 and May 2016. The CT scans were performed as part of routine clinical care within 45 days before study enrollment, and results were compared against clinical outcomes as well as patient-reported psychological assessments. Findings showed older, female patients tended to have lower muscle mass and radiodensity. Sixty-four percent of patients met the criteria for sarcopenia. Higher muscle radiodensity was significantly associated with better patient outcomes-including lower physical symptom burden and less depression and anxiety. However, it remains unclear whether poorer muscle radiodensity was a result of other symptoms that limit mobility, or vice versa.



Night Shift Schedule Causes Circadian Dysregulation of DNA Repair Genes and Elevated DNA Damage in Humans

New clues as to why night shift workers are at increased risk of developing certain types of cancer are presented in a new study (Journ of Pineal Research 2021; The study involved a controlled laboratory experiment that used healthy volunteers who were on simulated night shift or day shift schedules. Findings from the study suggest that night shifts disrupt natural 24-hour rhythms in the activity of certain cancer-related genes, making night shift workers more vulnerable to damage to their DNA while at the same time causing the body's DNA repair mechanisms to be mistimed to deal with that damage. As part of a partnership between the WSU Sleep and Performance Research Center and the U.S. Department of Energy's Pacific Northwest National Laboratory (PNNL), scientists worked with bioinformatics experts at PNNL to study the potential involvement of the biological clock, the body's built-in mechanism that keeps us on a 24-hour night and day cycle. The researchers hypothesized that the expression of genes associated with cancer might be rhythmic, and that night shift work might disrupt the rhythmicity of these genes. To test this, they conducted a simulated shift work experiment that had 14 participants spend 7 days inside a sleep laboratory. Half of them completed a 3-day simulated night shift schedule, while the other half were on a 3-day simulated day shift schedule. After completing their simulated shifts, all participants were kept in a constant routine protocol used to study humans' internally generated biological rhythms independent of any external influences. As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under constant light exposure and room temperature and were given identical snacks every hour. Every 3 hours a blood sample was drawn. Analyses of white blood cells taken from the blood samples showed that the rhythms of many of the cancer-related genes were different in the night shift condition compared to the day shift condition. Notably, genes related to DNA repair that showed distinct rhythms in the day shift condition lost their rhythmicity in the night shift condition. The researchers then looked at what the consequences of the changes in the expression of cancer-related genes might be. They found that white blood cells isolated from the blood of night shift participants showed more evidence of DNA damage than those of day shift participants. What's more, after the researchers exposed isolated white blood cells to ionizing radiation at two different times of day, cells radiated in the evening showed increased DNA damage in the night shift condition as compared to the day shift condition. This meant that white blood cells from night shift participants were more vulnerable to external damage from radiation, a known risk factor for DNA damage and cancer. The researchers' next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether unrepaired DNA damage builds up over time in night workers, which could ultimately increase the cancer risk. If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes. It could also be the basis for strategies to optimize the timing of cancer therapy so that treatment is administered when effectiveness is greatest and side effects are minimal, a procedure called chronotherapy that would need to be fine-tuned to the internal rhythms of night workers.