bims-meluca 2021-02-21 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–02–21
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α regulator.
STK1/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition.
Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression.
Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.
Relationship Between Nutritional Status and Quality of Life in Patients with Lung Cancer.
Serum macrophage inhibitory cytokine-1 as a clinical marker for non-small cell lung cancer.
Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.
Feasibility of a multimodal exercise, nutrition, and palliative care intervention in advanced lung cancer.

Cancer Sci. 2021 Jan 27.

Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α regulator.

Hisanori Isomura, Ayumu Taguchi, Taisuke Kajino, Naoya Asai, Masahiro Nakatochi, Seiichi Kato, Keiko Suzuki, Kiyoshi Yanagisawa, Motoshi Suzuki, Teruaki Fujishita, Tomoya Yamaguchi, Masahide Takahashi, Takashi Takahashi.

  We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.

Keywords:  EGFR; HIF-1α; ROR1; genetically engineered mouse model; lung adenocarcinoma

DOI:  https://doi.org/10.1111/cas.14825
Clin Cancer Res. 2020 Dec 15.

STK1/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition.

Piyada Sitthideatphaiboon, Ana Galan-Cobo, Marcelo V Negrao, Xiao Qu, Alissa Poteete, Fahao Zhang, Diane D Liu, Whitney E Lewis, Haley N Kemp, Jeff Lewis, Waree Rinsurongkawong, Uma Giri, J Jack Lee, Jianjun Zhang, Jack A Roth, Stephen Swisher, John V Heymach.

PURPOSE: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes.
EXPERIMENTAL DESIGN: We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain.
RESULTS: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy.
CONCLUSIONS: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-2859
Respir Res. 2021 Feb 17. 22(1): 58

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression.

Shengyu Hao, Xiaodan Zhu, Zilong Liu, Xiaodan Wu, Shanqun Li, Pan Jiang, Liyan Jiang.

   BACKGROUND: An adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis. So far, the relationship between OSA and lung CSCs has not been explored.
METHOD: In the present study, we established an orthotopic mouse model of primary lung cancer and utilized chronic intermittent hypoxia (CIH) exposure to mimic OSA status.
RESULTS: We observed that CIH endows lung cancer with greater metastatic potential, evidenced by increased tumor growth, tumor seeding, and upregulated CSC-related gene expression in the lungs. Notably, the transcription factor BTB and CNC homology 1 (Bach1), a key factor in responding to conditions of oxidative stress, is increased in lung cancer after CIH exposure in vitro and in vivo. Meanwhile, exposing lung cancer cells to CIH promoted cell proliferation, clonal diversity, induced stem-like cell marker expression, and gave rise to CSCs at a relatively higher frequency. Furthermore, the increase of mitochondrial ROS (mtROS) and CSC-marker expression induced by CIH exposure was abolished in Bach1 shRNA-treated lung cancer cells.
CONCLUSIONS: Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.

Keywords:  Bach1; Cancer stem cells; Chronic intermittent hypoxia; Lung cancer; Obstructive sleep apnea

DOI:  https://doi.org/10.1186/s12931-021-01655-6
Cell Death Dis. 2021 Feb 16. 12(2): 189

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Muyun Liu, Dan Wang, Yongde Luo, Lianghao Hu, Yawei Bi, Juntao Ji, Haojie Huang, Guoqiang Wang, Liang Zhu, Jianjia Ma, Eunice Kim, Catherine K Luo, James L Abbruzzese, Xiaokun Li, Vincent W Yang, Zhaoshen Li, Weiqin Lu.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

DOI: https://doi.org/10.1038/s41419-021-03473-6
Cancer Manag Res. 2021 ;13 1407-1416

Relationship Between Nutritional Status and Quality of Life in Patients with Lung Cancer.

Jacek Polański, Beata Jankowska-Polańska, Grzegorz Mazur.

   Introduction: Malnutrition is often co-occur in patients with advanced cancer and are associated with poorer response to treatment therapy and decrease significantly the quality of life (QoL). There is little evidence regarding the relationship between nutritional status and QoL in this patient group.
Purpose of the Study: To assess the relationship between nutritional status and QoL in patients with lung cancer.
Methods: Our cross-sectional, descriptive study included 310 patients. Only standardized instruments were used to perform the study: Mini Nutritional Assessment (MNA) to assess nutritional status and The European Organization for Research and Treatment of Cancer Quality of Life Core-30 (EORTC-QLQ-C30) and Lung Cancer-13 (LC-13) to assess the QoL.
Results: The mean age in the study group was 63.77±9.43. 18.71% of patients were malnourished 44.19% at risk of malnutrition and 37.1% of patients had normal nutritional status. Clinical characteristics showed that 75% of respondents had been diagnosed with non-small-cell lung carcinoma, with an average duration of illness of 1-2 years. Nearly all patients received symptomatic treatment, and one in two had undergone surgery. At subsequent stages, QoL was analyzed in three groups depending on nutritional status risk. Malnourished patients had a lower quality of life and greater severity of cancer symptoms than those with a normal nutritional status (p<0.001). In regression analysis, nutritional status has a significant impact on all QLQ-C30 functional scales. Regression parameters are positive, indicating that better nutritional status is associated with better functioning in specific QLQ domains.
Conclusion: A considerable proportion of lung cancer patients are either malnourished or at risk of malnutrition. Malnutrition correlates negatively with QoL and increases symptom severity. Malnutrition is an independent determinant of lower QoL.
Implications for Practice: Nutritional assessment should be accompanied by QoL evaluation, so that nutritional interventions can be optimized based on a patient's individual requirements.

Keywords:  lung cancer; malnutrition; quality of life

DOI:  https://doi.org/10.2147/CMAR.S287551
J Cell Mol Med. 2021 Feb 18.

Serum macrophage inhibitory cytokine-1 as a clinical marker for non-small cell lung cancer.

Chunhua Xu, Li Li, Wei Wang, Qian Zhang, Xiuwei Zhang, Rusong Yang.

  The aim of this study was to investigate the value of serum macrophage inhibitory factor-1 (MIC-1) level in patients with non-small cell lung cancer (NSCLC). Serum samples from 296 patients with NSCLC and 240 healthy controls were collected. The levels of serum MIC-1 were determined by ELISA. The serum MIC-1 levels in NSCLC patients were higher than that of the controls (P <.001). Univariate and multivariate Cox regression analysis showed that serum MIC-1 was an independent prognostic indicator of OS and PFS. Serum MIC-1 is a valuable biomarker for the diagnosis and prognosis of NSCLC.

Keywords:  diagnosis; macrophage inhibitory cytokine-1; non-small cell lung cancer; prognosis

DOI:  https://doi.org/10.1111/jcmm.16360
Nature. 2021 Feb 15.

Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

McLane J Watson, Paolo D A Vignali, Steven J Mullett, Abigail E Overacre-Delgoffe, Ronal M Peralta, Stephanie Grebinoski, Ashley V Menk, Natalie L Rittenhouse, Kristin DePeaux, Ryan D Whetstone, Dario A A Vignali, Timothy W Hand, Amanda C Poholek, Brett M Morrison, Jeffrey D Rothstein, Stacy G Wendell, Greg M Delgoffe.

Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4-6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

DOI: https://doi.org/10.1038/s41586-020-03045-2
BMC Cancer. 2021 Feb 13. 21(1): 159

Feasibility of a multimodal exercise, nutrition, and palliative care intervention in advanced lung cancer.

Manuel Ester, S Nicole Culos-Reed, Amane Abdul-Razzak, Julia T Daun, Delaney Duchek, George Francis, Gwyn Bebb, Jennifer Black, Audra Arlain, Chelsia Gillis, Lyle Galloway, Lauren C Capozzi.

   BACKGROUND: Advanced lung cancer patients face significant physical and psychological burden leading to reduced physical function and quality of life. Separately, physical activity, nutrition, and palliative symptom management interventions have been shown to improve functioning in this population, however no study has combined all three in a multimodal intervention. Therefore, we assessed the feasibility of a multimodal physical activity, nutrition, and palliative symptom management intervention in advanced lung cancer.
METHODS: Participants received an individually tailored 12-week intervention featuring in-person group-based exercise classes, at-home physical activity prescription, behaviour change education, and nutrition and palliative care consultations. Patients reported symptom burden, energy, and fatigue before and after each class. At baseline and post-intervention, symptom burden, quality of life, fatigue, physical activity, dietary intake, and physical function were assessed. Post-intervention interviews examined participant perspectives.
RESULTS: The multimodal program was feasible, with 44% (10/23) recruitment, 75% (75/100) class attendance, 89% (8/9) nutrition and palliative consult attendance, and 85% (17/20) assessment completion. Of ten participants, 70% (7/10) completed the post-intervention follow-up. Participants perceived the intervention as feasible and valuable. Physical activity, symptom burden, and quality of life were maintained, while tiredness decreased significantly. Exercise classes prompted acute clinically meaningful reductions in fatigue, tiredness, depression, pain, and increases in energy and well-being.
CONCLUSION: A multimodal physical activity, nutrition, and palliative symptom management intervention is feasible and shows potential benefits on quality of life that warrant further investigation in a larger cohort trial.
TRIAL REGISTRATION: NCT04575831 , Registered 05 October 2020 - Retrospectively registered.

Keywords:  Advanced lung cancer; Exercise oncology; Nutrition; Quality of life; Supportive cancer care; Symptom management

DOI:  https://doi.org/10.1186/s12885-021-07872-y