bims-meluca 2023-01-22 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–01–22
five papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

CMTM6 is highly expressed in lung adenocarcinoma and can be used as a biomarker of a poor diagnosis.
LKB1 Loss Assessed by Immunohistochemistry as a Prognostic Marker to First-Line Therapy in Advanced Non-Small-Cell Lung Cancer.
Serum proteomics profiling identifies a preliminary signature for the diagnosis of early-stage lung cancer.
A Subset of PD-1-Expressing CD56bright NK Cells Identifies Patients with Good Response to Immune Checkpoint Inhibitors in Lung Cancer.
Over-expression of USP15/MMP3 predict poor prognosis and promote growth, migration in non-small cell lung cancer cells.

PeerJ. 2023 ;11 e14668

CMTM6 is highly expressed in lung adenocarcinoma and can be used as a biomarker of a poor diagnosis.

Daqi Jia, Li Xiong, Honggang Xue, Jidong Li.

   Background: CMTM6 which is chemokine-like factor (CKLF)-like Marvel transmembrane domain containing family member 6 is involved in the occurrence and progression of various tumors. However, the role of CMTM6 is still unclear in lung adenocarcinoma (LUAD).
Methods: Immunohistochemical, Western blotting and RT‒PCR methods were used to detect the expression of CMTM6 in LUAD. Cox regression and the Kaplan‒Meier method were performed to assess overall survival. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints. The sensitivity to chemotherapy agents was estimated using the pRRophetic package.
Results: In LUAD, the expression of CMTM6 was obviously upregulated and was significantly associated with T stage (p = 0.008) and lymph node metastasis (p = 0.018). Multivariate Cox regression analysis demonstrated that CMTM6 was a specialty prognostic risk factor. Based on GSEA enrichment analysis, we found that high expression of CMTM6 is associated with multiple immune signaling pathways. The group with high CMTM6 expression showed a positive association with various types of tumor-infiltrating cells. Moreover, a total of 36 chemotherapeutic drugs were significantly correlated with the expression of CMTM6. Among them, two chemotherapeutic drugs had better therapeutic effects in the high CMTM6 expression group, while 34 chemotherapeutic drugs had therapeutic effects in the low CMTM6 expression group.
Conclusion: This study confirmed that CMTM6 is highly expressed in LUAD and is a new independent poor prognostic factor. In addition, the high expression of CMTM6 is closely related to the tumor microenvironment and immunotherapy, providing new ideas for the treatment of posterior LUAD.

Keywords:  CMTM6; Immune cell; Immunotherapy; Lung cancer; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.7717/peerj.14668
Curr Oncol. 2022 Dec 26. 30(1): 333-343

LKB1 Loss Assessed by Immunohistochemistry as a Prognostic Marker to First-Line Therapy in Advanced Non-Small-Cell Lung Cancer.

Alejandro Avilés-Salas, Diego A Díaz-García, Luis Lara-Mejía, Andrés F Cardona, Mario Orozco-Morales, Rodrigo Catalán, Norma Y Hernández-Pedro, Eduardo Rios-Garcia, Maritza Ramos-Ramírez, Oscar Arrieta.

  (1) Background: Liver kinase B1 (LKB1) is a tumor suppressor gene involved in cell growth and metabolism. However, its alterations are not routinely assessed for guiding therapy in clinical practice. We assessed LKB1 expression by immunohistochemistry as a potential biomarker. (2) Methods: This bicentric retrospective cohort study analyzed data from patients with advanced NSCLC who initiated platinum-based chemotherapy or epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) between January 2016 and December 2020. Kaplan-Meier and Cox regression models were used for survival curves and multivariate analysis. (3) Results: 110 patients were evaluated, and the clinical stage IV predominated the lung adenocarcinoma histology. LKB1 loss was observed in 66.3% of cases. LKB1 loss was associated with non-smokers, the absence of wood smoke exposure and an EGFR wild-type status. The median progression-free survival (PFS) and overall survival (OS) in the population were 11.1 and 26.8 months, respectively, in the loss group, compared with cases exhibiting a positive expression. After an adjustment by age, smoking status, Eastern Cooperative Oncology Group Performance Score (ECOG-PS), EGFR status and type of administered therapy, LKB1 loss was significantly associated with worse PFS and OS. (4) Conclusion: Patients with an LKB1 loss had worse clinical outcomes. This study warrants prospective assessments to confirm the prognostic role of the LKB1 expression in advanced NSCLC.

Keywords:  STK11; advanced NSCLC; immunohistochemistry; lung cancer; prognostic biomarker

DOI:  https://doi.org/10.3390/curroncol30010027
Proteomics Clin Appl. 2023 Jan 16. e2200093

Serum proteomics profiling identifies a preliminary signature for the diagnosis of early-stage lung cancer.

Roberto Gasparri, Roberta Noberini, Alessandro Cuomo, Avinash Yadav, Davide Tricarico, Carola Salvetto, Patrick Maisonneuve, Valentina Caminiti, Giulia Sedda, Angela Sabalic, Tiziana Bonaldi, Lorenzo Spaggiari.

   PURPOSE: Lung cancer is the most common cause of death from cancer worldwide, largely due to late diagnosis. Thus, there is an urgent need to develop new approaches to improve the detection of early-stage lung cancer, which would greatly improve patient survival.
EXPERIMENTAL DESIGN: The quantitative protein expression profiles of microvesicles isolated from the sera from 46 lung cancer patients and 41 high-risk non-cancer subjects were obtained using a mass spectrometry method based on a peptide library matching approach.
RESULTS: We identified 33 differentially expressed proteins that allow discriminating the two groups. We also built a machine learning model based on serum protein expression profiles that can correctly classify the majority of lung cancer cases and that highlighted a decrease in the levels of Arysulfatase A (ARSA) as the most discriminating factor found in tumors.
CONCLUSIONS AND CLINICAL RELEVANCE: Our study identified a preliminary, non-invasive protein signature able to discriminate with high specificity and selectivity early-stage lung cancer patients from high-risk healthy subjects. These results provide the basis for future validation studies for the development of a non-invasive diagnostic tool for lung cancer. This article is protected by copyright. All rights reserved.

Keywords:  biomarker; early diagnosis; lung cancer; machine learning; mass spectrometry; serum

DOI:  https://doi.org/10.1002/prca.202200093
Cancers (Basel). 2023 Jan 04. pii: 329. [Epub ahead of print]15(2):

A Subset of PD-1-Expressing CD56bright NK Cells Identifies Patients with Good Response to Immune Checkpoint Inhibitors in Lung Cancer.

Marta Gascón-Ruiz, Ariel Ramírez-Labrada, Rodrigo Lastra, Luis Martínez-Lostao, J Ramón Paño-Pardo, Andrea Sesma, María Zapata-García, Alba Moratiel, Elisa Quílez, Irene Torres-Ramón, Alfonso Yubero, María Pilar Domingo, Patricia Esteban, Eva M Gálvez, Julián Pardo, Dolores Isla.

  (1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3-CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3-CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3-CD16-PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size.

Keywords:  NK cells; T lymphocytes; biomarkers; immunotherapy; lung cancer

DOI:  https://doi.org/10.3390/cancers15020329
Cancer Genet. 2023 Jan 07. pii: S2210-7762(23)00001-7. [Epub ahead of print]272-273 9-15

Over-expression of USP15/MMP3 predict poor prognosis and promote growth, migration in non-small cell lung cancer cells.

Weiwei Chen, Daguang Ni, Hailin Zhang, Xia Li, Youqin Jiang, Jixiang Wu, Yan Gu, Mingcheng Gao, Woda Shi, Jianxiang Song, Wenyu Shi.

  Aberrant ubiquitin modifications caused by an imbalance in the activities of ubiquitinases and de-ubiquitinases are emerging as important mechanisms underlying non-small cell lung cancer (NSCLC) progression. The deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) has been identified as an important factor in oncogenesis and a potential therapeutic target. However, the expression profile and function of USP15 in NSCLC remain elusive. In the present study, we investigated the expression pattern and the potential biological functions of USP15 in NSCLC both in cells and animal models. Our data revealed that USP15 was highly expressed in NSCLC tissues and cells compared with normal counterpart. We subsequently knocked down USP15 expression in two NSCLC cell lines, which significantly suppressed cell proliferation. In addition, knocking down USP15 expression reduced NSCLC cell migration and invasion according to the results from Matrigel-Transwell analysis. NSCLC animal model results showed that USP15 knockdown also reduced NSCLC size. Biochemical analysis revealed that USP15 knockdown inhibited matrix metalloproteinase (MMP)3 and MMP9 expression. Furthermore, high levels of USP15 and MMP3 expression were associated with poor prognosis in NSCLC. In conclusion, the results from the present study suggest that the high expression of USP15 promotes NSCLC tumorigenesis. Therefore, it is proposed that USP15 and MMPs may represent novel biomarkers for NSCLC progression and prognosis.

Keywords:  MMP; NSCLC; USP15; growth; invasion; prognosis

DOI:  https://doi.org/10.1016/j.cancergen.2023.01.001