bims-meluca 2023-11-12 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–11–12
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.
Modified Controlling Nutritional Status (mCONUT) serves as a promising prognostic factor in patients with cancer cachexia.
High-fat diet induces C-reactive protein secretion, promoting lung adenocarcinoma via immune microenvironment modulation.
Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism.
Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.
FUT3 facilitates glucose metabolism of lung adenocarcinoma via activation of NF-κB pathway.
CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer.
Pretreatment albumin is a prognostic and predictive biomarker for response to atezolizumab across solid tumors.

Cancer Res. 2023 11 07.

Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.

Pasquale Saggese, Aparamita Pandey, Martín Alcaraz, Eileen Fung, Abbie Hall, Jane Yanagawa, Erika F Rodriguez, Tristan R Grogan, Giorgio Giurato, Giovanni Nassa, Annamaria Salvati, Orian S Shirihai, Alessandro Weisz, Steven M Dubinett, Claudio Scafoglio.

Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA-approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be re-purposed for lung cancer. Despite the anti-tumor effects of SGLT2 inhibition, tumors eventually escape treatment. Here, we studied the mechanisms of resistance to glucose metabolism-targeting treatments. Glucose restriction in LUAD and other tumors induced cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation caused a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. The de-differentiated phenotype depended on unbalanced EZH2 activity that suppressed prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial-to-mesenchymal transition. Finally, a HIF1α-dependent transcriptional signature of genes up-regulated by low glucose correlated with prognosis in human LUAD. Overall, this study furthers current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying targets to prevent the development of resistance to therapies targeting glucose metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1148
Nutrition. 2023 Sep 19. pii: S0899-9007(23)00257-5. [Epub ahead of print]117 112229

Modified Controlling Nutritional Status (mCONUT) serves as a promising prognostic factor in patients with cancer cachexia.

Xi Zhang, Jia-Xin Huang, Meng Tang, Qi Zhang, Li Deng, Chun-Hua Song, Wei Li, Han-Ping Shi, Ming-Hua Cong.

   BACKGROUND: Malnutrition and systemic inflammation are considered 2 hallmarks of cancer cachexia. Our study aimed to construct a modified Controlling Nutritional Status by introducing C-reactive protein as an inflammatory parameter and investigate its prognostic value in patients with cancer cachexia.
METHODS: This multicenter cohort study included 5221 patients with cancer, among whom 1719 were diagnosed with cachexia. Concordance index and receiver operating characteristic curves were used to compare prognostic values between the 2 systems. The primary outcome was overall survival, and comprehensive survival analyses were performed. The secondary outcomes were short-term survival, malnutrition, and quality of life.
RESULTS: During the median follow-up of 17.47 mo, 813 deaths were recorded. The modified Controlling Nutritional Status was more accurate than Controlling Nutritional Status in predicting survival in patients with cancer cachexia. Patients in the high Controlling Nutritional Status/modified Controlling Nutritional Status group had a significantly shorter overall survival. Multivariate Cox analysis confirmed high Controlling Nutritional Status (hazard ratio = 1.34, 95% CI, 1.13-1.58; P < 0.001) and modified Controlling Nutritional Status (hazard ratio = 1.46; 95% CI, 1.26-1.69; P < 0.001) were independent risk factors for survival, adjusting for confounders. In subgroup analyses, a high modified Controlling Nutritional Status score had a significantly negative effect on survival in cachexia patients with upper gastrointestinal and colorectal cancer, especially for advanced-stage (stages III and IV) patients. The risk of short-term mortality and experiencing malnutrition rose to 1.48 and 1.13 times, respectively, in the high modified Controlling Nutritional Status group, as well as that for poorer life quality.
CONCLUSION: The modified Controlling Nutritional Status group comprehensively reflects nutritional, immune, and inflammatory status and serves as a powerful prognostic scoring system in patients with cancer cachexia.

Keywords:  Cancer Cachexia; Controlling Nutritional Status; Malnutrition; Prognosis; Systemic inflammation

DOI:  https://doi.org/10.1016/j.nut.2023.112229
Dis Model Mech. 2023 Nov 01. pii: dmm050360. [Epub ahead of print]16(11):

High-fat diet induces C-reactive protein secretion, promoting lung adenocarcinoma via immune microenvironment modulation.

Wei-Lun Hsu, Yun-Ting Hsieh, Wei-Ming Chen, Min-Hui Chien, Wei-Jia Luo, Jung-Hsuan Chang, Kevin Devlin, Kang-Yi Su.

  To understand the effects of a high-fat diet (HFD) on lung cancer progression and biomarkers, we here used an inducible mutant epidermal growth factor receptor (EGFR)-driven lung cancer transgenic mouse model fed a regular diet (RD) or HFD. The HFD lung cancer (LC-HFD) group exhibited significant tumor formation and deterioration, such as higher EGFR activity and proliferation marker expression, compared with the RD lung cancer (LC-RD) group. Transcriptomic analysis of the lung tissues revealed that the significantly changed genes in the LC-HFD group were highly enriched in immune-related signaling pathways, suggesting that an HFD alters the immune microenvironment to promote tumor growth. Cytokine and adipokine arrays combined with a comprehensive analysis using meta-database software indicated upregulation of C-reactive protein (CRP) in the LC-HFD group, which presented with increased lung cancer proliferation and metastasis; this was confirmed experimentally. Our results imply that an HFD can turn the tumor growth environment into an immune-related pro-tumorigenic microenvironment and demonstrate that CRP has a role in promoting lung cancer development in this microenvironment.

Keywords:  CRP; High-fat diet; Lung cancer; Mutant EGFR transgenic mice; Tumor microenvironment

DOI:  https://doi.org/10.1242/dmm.050360
BMC Med. 2023 11 03. 21(1): 417

Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism.

Dan Shi, Gaofeng Fang, Qianyao Chen, Jianling Li, Xiongzhong Ruan, Xuemei Lian.

   BACKGROUND: Accumulating evidence has suggested an oncogenic effect of diurnal disruption on cancer progression. To test whether targeting circadian rhythm by dietary strategy suppressed lung cancer progression, we adopted 6-h time-restricted feeding (TRF) paradigm to elucidate whether and how TRF impacts lung cancer progression.
METHODS: This study used multiple lung cancer cell lines, two xenograft mouse models, and a chemical-treated mouse lung cancer model. Stable TIM-knockdown and TIM-overexpressing A549 cells were constructed. Cancer behaviors in vitro were determined by colony formation, EdU proliferation, wound healing, transwell migration, flow cytometer, and CCK8 assays. Immunofluorescence, pathology examinations, and targeted metabolomics were also used in tumor cells and tissues. mCherry-GFP-LC3 plasmid was used to detect autophagic flux.
RESULTS: We found for the first time that compared to normal ad libitum feeding, 6-h TRF inhibited lung cancer progression and reprogrammed the rhythms of metabolites or genes involved in glycolysis and the circadian rhythm in tumors. After TRF intervention, only timeless (TIM) gene among five lung cancer-associated clock genes was found to consistently align rhythm of tumor cells to that of tumor tissues. Further, we demonstrated that the anti-tumor effect upon TRF was partially mediated by the rhythmic downregulation of the TIM and the subsequent activation of autophagy. Combining TRF with TIM inhibition further enhanced the anti-tumor effect, comparable to treatment efficacy of chemotherapy in xenograft model.
CONCLUSIONS: Six-hour TRF inhibits lung cancer progression and reshapes circadian metabolism, which is partially mediated by the rhythmic downregulation of the TIM and the subsequent upregulation of autophagy.

Keywords:  Autophagy; Circadian rhythm; Lung cancer; Progression; TIM; Time-restricted feeding

DOI:  https://doi.org/10.1186/s12916-023-03131-y
Nat Commun. 2023 Nov 08. 14(1): 6764

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.

Igor Dolgalev, Hua Zhou, Nina Murrell, Hortense Le, Theodore Sakellaropoulos, Nicolas Coudray, Kelsey Zhu, Varshini Vasudevaraja, Anna Yeaton, Chandra Goparaju, Yonghua Li, Imran Sulaiman, Jun-Chieh J Tsay, Peter Meyn, Hussein Mohamed, Iris Sydney, Tomoe Shiomi, Sitharam Ramaswami, Navneet Narula, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw A Smolen, Wei-Yi Cheng, James Cai, Salman Punekar, Vamsidhar Velcheti, Daniel H Sterman, J T Poirier, Ben Neel, Kwok-Kin Wong, Luis Chiriboga, Adriana Heguy, Thales Papagiannakopoulos, Bettina Nadorp, Matija Snuderl, Leopoldo N Segal, Andre L Moreira, Harvey I Pass, Aristotelis Tsirigos.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

DOI: https://doi.org/10.1038/s41467-023-42327-x
BMC Pulm Med. 2023 Nov 09. 23(1): 436

FUT3 facilitates glucose metabolism of lung adenocarcinoma via activation of NF-κB pathway.

Lanlan Lin, Xiaohui Chen, Guofu Lin, Luyang Chen, Yuan Xu, Yiming Zeng.

   OBJECTIVE: Fucosyltransferases (FUTs) molecules have been identified to be involved in carcinogenesis of malignant tumors. Nevertheless, the biological function of fucosyltransferases-3 (FUT3) in lung adenocarcinoma (LUAD) malignant phenotype remains unclear. Herein, we investigated the association between FUT3 and LUAD pathological process.
METHODS: Immunochemistry, RT-qPCR and western blot assays were conducted to evaluate the expression of FUT3 in LUAD and corresponding adjacent tissues. The prognostic value of FUT3 was assessed via Kaplan‑Meier plotter database. The biological process and potential mechanism of FUT3 in LUAD were conducted via GSEA. Additionally, immunofluorescence and metabolite activity detection were performed to determine the potential role of FUT3 in LUAD glucose metabolism. The active biomarkers associated with NF-κB signaling pathway were detected via western blot. Subcutaneous tumor model was conducted to analyze the effect of FUT3 on tumorigenesis of LUAD.
RESULTS: FUT3 was remarkably upregulated in LUAD tissues compared with adjacent tissues from individuals. FUT3 overexpression may predict poor prognosis of LUAD patients. Knockdown of FUT3 significantly inhibited tumor proliferation, migration and glucometabolic alteration in LUAD cells. Moreover, GSEA demonstrated that elevated FUT3 was positively related to NF-κB signaling pathway. Additionally, in vitro and in vivo assays also indicated that downregulation of FUT3 resulted in the suppression of oncogenesis and glucose metabolism via inactivation of NF-κB pathway.
CONCLUSION: Our findings demonstrated that FUT3 was involved in glucometabolic process and tumorigenesis of LUAD via NF-κB signaling pathway. FUT3 may be an optimal target for diagnosis and treatment of LUAD patients.

Keywords:  FUT3; Glucose metabolism; Lung adenocarcinoma; NF-κB pathway

DOI:  https://doi.org/10.1186/s12890-023-02688-x
Cancer Res. 2023 Nov 07.

CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer.

Anirudh Prahallad, Andreas Weiss, Hans Voshol, Grainne Kerr, Kathleen Sprouffske, Tina Yuan, David Ruddy, Morgane Meistertzheim, Malika Kazic-Legueux, Tina Kottarathil, Michelle Piquet, Yichen Cao, Laetitia Martinuzzi-Duboc, Alexandra Buhles, Flavia Alder, Salvatore Mannino, Luca Tordella, Laurent Sansregret, Sauveur-Michel Maira, Diana Graus Porta, Carmine Fedele, Saskia M Brachmann.

Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 co-inhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1127
Clin Transl Immunology. 2023 ;12(11): e1472

Pretreatment albumin is a prognostic and predictive biomarker for response to atezolizumab across solid tumors.

Jonas Saal, Jörg Ellinger, Manuel Ritter, Peter Brossart, Michael Hölzel, Niklas Klümper, Tobias Bald.

   Objectives: Reliable predictive biomarkers for response to immune checkpoint inhibition (ICI) are lacking. Pretreatment serum albumin, a known prognostic and predictive factor in ICI-treated patients, has been proposed as a potential pharmacokinetic surrogate marker for anti-PD1/PD-L1 antibodies, as it shares a homeostatic pathway with IgG. However, this hypothesis is currently based on theoretical considerations and limited evidence from retrospective data. Therefore, we comprehensively investigated the prognostic and predictive value of pretreatment albumin and its relationship with anti-PD-L1 IgG levels.
Methods: We analysed pretreatment albumin and atezolizumab serum levels and clinical response in four trials (IMvigor210, IMvigor211, IMmotion151 and OAK) of patients with metastatic lung-, renal- or urothelial cancer who received atezolizumab alone or in combination.
Results: A total of 3391 patients were analysed. Correlation between serum albumin and atezolizumab levels was weak (Pearson's coefficient 0.23). We found a strong prognostic value for pretreatment serum albumin across all trials. Both atezolizumab serum levels and serum albumin were independently correlated with overall survival. Importantly, in the three randomised phase III clinical trials, the survival benefit for immunotherapy compared with the active comparator arm was limited to patients with pretreatment serum albumin > 35 g L-1.
Conclusion: Our data do not support the hypothesis that albumin serves as a surrogate for atezolizumab pharmacokinetics. However, we show that albumin on its own exerts strong prognostic value for patients treated with immunotherapy. As benefit from immunotherapy was limited to patients with normal/elevated serum albumin levels, baseline albumin could potentially be used as a predictive marker for immune checkpoint inhibition.

Keywords:  NSCLC; RCC; UC; albumin; biomarkers; immunotherapy

DOI:  https://doi.org/10.1002/cti2.1472