bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024‒03‒24
five papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge



  1. J Exp Clin Cancer Res. 2024 Mar 16. 43(1): 82
      The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of "liquid biopsy"‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.
    Keywords:  Biomarker; Immunotherapy; Liquid biopsy; NSCLC; Peripheral blood
    DOI:  https://doi.org/10.1186/s13046-024-02969-1
  2. Cancer Metab. 2024 Mar 21. 12(1): 9
      Serine and glycine give rise to important building blocks in proliferating cells. Both amino acids are either synthesized de novo or taken up from the extracellular space. In lung cancer, serine synthesis gene expression is variable, yet, expression of the initial enzyme, phosphoglycerate dehydrogenase (PHGDH), was found to be associated with poor prognosis. While the contribution of de novo synthesis to serine pools has been shown to be enhanced by serine starvation, the impact of glucose deprivation, a commonly found condition in solid cancers is poorly understood. Here, we utilized a stable isotopic tracing approach to assess serine and glycine de novo synthesis and uptake in different lung cancer cell lines and normal bronchial epithelial cells in variable serine, glycine, and glucose conditions. Under low glucose supplementation (0.2 mM, 3-5% of normal plasma levels), serine de novo synthesis was maintained or even activated. As previously reported, also gluconeogenesis supplied carbons from glutamine to serine and glycine under these conditions. Unexpectedly, low glucose treatment consistently enhanced serine to glycine conversion, along with an up-regulation of the mitochondrial one-carbon metabolism enzymes, serine hydroxymethyltransferase (SHMT2) and methylenetetrahydrofolate dehydrogenase (MTHFD2). The relative contribution of de novo synthesis greatly increased in low serine/glycine conditions. In bronchial epithelial cells, adaptations occurred in a similar fashion as in cancer cells, but serine synthesis and serine to glycine conversion, as assessed by label enrichments and gene expression levels, were generally lower than in (PHGDH positive) cancer cells. In summary, we found a variable contribution of glucose or non-glucose carbon sources to serine and glycine and a high adaptability of the downstream one-carbon metabolism pathway to variable glucose supply.
    Keywords:  Glycine; Lung cancer; Metabolism; Serine; Starvation
    DOI:  https://doi.org/10.1186/s40170-024-00337-3
  3. Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2319429121
      Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.
    Keywords:  SAT1; glutamine metabolism; lung cancer; polyamine catabolism
    DOI:  https://doi.org/10.1073/pnas.2319429121
  4. J Thorac Dis. 2024 Feb 29. 16(2): 1424-1437
      Background: Antiangiogenetic therapy is one of the effective strategies for non-small cell lung cancer (NSCLC) treatment. Four-and-a-half LIM-domain protein 2 (FHL2) serves as a key function in cell growth and metastasis of multiple cancers, but the role of FHL2 in NSCLC angiogenesis has not been intensely examined.Methods: FHL2 expression in NSCLC tissues and cell lines and its correlation with patients prognosis were investigated by using The Cancer Genome Atlas (TCGA) database and quantitative polymerase chain reaction (qPCR). Cell Counting Kit-8 (CCK-8) assay, EdU (5-ethynyl-2'-deoxyuridine) assay, and a xenograft model were used to investigate the effects of FHL2 on NSCLC progression in vitro and in vivo. CCK-8, wound-healing, Transwell invasion, tube formation, and permeability assays were performed to determine the roles of FHL2 in angiogenesis and vascular permeability. Vascular endothelial growth factor A (VEGFA) enzyme-linked immunosorbent assay (ELISA) assay, Western blot analysis, and MK-2206 were used to investigate the specific mechanism mediated by FHL2.
    Results: We demonstrated that FHL2 was significantly upregulated in NSCLC tissues and cell lines and was associated with poor prognosis. FHL2 overexpression enhanced the cell viability of NSCLC cells, as well as the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, we determined that FHL2 activated the AKT-mTOR signaling pathway in HUVECs by promoting VEGFA secretion from NSCLC cells, thereby inducing angiogenesis and vascular leakiness. We further confirmed that FHL2 also promoted NSCLC tumor growth in vivo.
    Conclusions: Our study revealed the role of FHL2 in NSCLC and the mechanism by which FHL2 promotes NSCLC tumorigenesis, providing novel insights into targeted therapy for NSCLC.
    Keywords:  Non-small cell lung cancer (NSCLC); angiogenesis; four-and-a-half LIM-domain protein 2 (FHL2); permeability
    DOI:  https://doi.org/10.21037/jtd-23-1975
  5. JCO Precis Oncol. 2024 Mar;8 e2300555
      PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions.PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1.
    RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424).
    CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.
    DOI:  https://doi.org/10.1200/PO.23.00555