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. 2023 Oct;13(10):e1391.
doi: 10.1002/ctm2.1391.

TIMP1 is an early biomarker for detection and prognosis of lung cancer

Ezequiel Dantas  1   2 , Anirudh Murthy  1   2 , Tanvir Ahmed  1   2 , Mujmmail Ahmed  1   2 , Shakti Ramsamooj  1   2 , Maurice A Hurd  1   2 , Tiffany Lam  3 , Murtaza Malbari  4 , Christopher Agrusa  3 , Olivier Elemento  2   5   6 , Chen Zhang  7 , Darryl J Pappin  8 , Timothy E McGraw  2   5   9 , Brendon M Stiles  10 , Nasser K Altorki  2   5 , Marcus D Goncalves  1   2
Affiliations

TIMP1 is an early biomarker for detection and prognosis of lung cancer

Ezequiel Dantas et al. Clin Transl Med. 2023 Oct.

Abstract

Background: Lung cancer remains the major cause of cancer-related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up.

Methods: Using bead-based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single-cell RNA-seq and bulk RNA-seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases.

Results: We found that TIMP1 is a tumour-secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients.

Conclusion: TIMP1 is a suitable biomarker for lung cancer detection.

Keywords: TIMP1; biomarkers; lung cancer; prognosis.

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Conflict of interest statement

M.D.G. reports personal fees from Novartis, Pfizer and Scorpion Therapeutics for work unrelated to this topic. M.D.G. is co‐founder and shareholder of Faeth Therapeutics. N.K.A. has equity in Angiocrine Bioscience. O.E. is supported by Janssen, J&J, Astra‐Zeneca, Volastra and Eli Lilly research grants. He is a scientific advisor and an equity holder in Freenome, Owkin, Volastra Therapeutics and One Three Biotech and a paid scientific advisor to Champions Oncology. T.E.M. receives research funding from Janssen and from Pfizer, Inc. B.M.S. is a consultant for Pfizer, AstraZeneca and Flame Biosciences. B.M.S. is on the advisory board or a speaker for Pfizer, AstraZeneca, BMS and Genentech and is a Board member of the Lung Cancer Research Foundation and the AATS Foundation Council. B.M.S. discloses holding stock or salary in Pfizer, PPD (Pharmaceutical Product Development). B.M.S. is a consultant at Flame Biosciences and Galvanize Therapeutics. B.M.S.’s wife is an employee of and has financial interest in Xalud Therapeutics. All other authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
TIMP1 is a biomarker of lung cancer in the KL mice. (A and B) Dot‐Blot of the cytokines that were significantly different when compared to non‐induced mice (WT) in the tumour/lung (A) or serum (B), fold change (FC) is cancer/WT. (C) Concentration levels of TIMP1 in the tumour (n = 89) or normal lungs (n = 29, left) and serum (WT, n = 30, KL, n = 127, right) of a larger cohort of KL mice by Luminex. (D) ROC curve of TIMP1 in the serum and tumour of KL mice used in panel (C). Circles show chosen thresholds (t) of TIMP1(pg/mL) used to calculate specificity(sp) and sensitivity(se). (E) Correlation between total lung mass and TIMP1 concentration in the tumour and serum of the KL mice. (F–H) Representative immunohistochemistry (IHC) for TIMP1 expression in the tumours of the KL mice. Comparisons in (A), (B) and (C) were made using Wilcoxon test (*p ≤ 0.05).
FIGURE 2
FIGURE 2
TIMP1 levels in serum and tumour correlate with unfavorable survival probability in mice. (A and B) Kaplan–Meier survival probability graphs using TIMP1 levels in the serum (n = 85) (A) and tumour (n = 32) (B) as a variable factor. (C) TIMP1 levels in the serum of NT, (n = 27) and KL (n = 52) mice at week 5 post tumour induction. (D) Kaplan–Meier survival probability graph using TIMP1 levels at week 5 as a variable factor (n = 41). Comparison in C was made using Wilcoxon test (*p ≤ 0.05). Comparisons for the KM plots in (A), (B) and (D) were done using the Log‐rank Mantel‐Cox test (*p ≤ 0.05).
FIGURE 3
FIGURE 3
TIMP1 is a biomarker for lung cancer in humans. (A) Concentration of TIMP1 in the plasma of healthy controls (n = 39), patients with ‘other’ non‐oncologic thoracic diseases (n = 26), and lung cancer patients (n = 122). (B) ROC curve using TIMP1 concentration in the plasma of healthy controls and lung cancer patients of panel (A). Circle shows chosen threshold (t) of TIMP1(ng/mL) in plasma used to calculate specificity(sp) and sensitivity(se). (C) Relative expression of TIMP1 mRNA by qPCR in healthy margins (n = 26) and tumours (n = 26) from lung cancer patients. (D). TIMP1 expression (FPKM) in normal lung (n = 10), non‐solid nodules (n = 23) and solid nodules using RNA‐seq (n = 22). (E) Representative microphotographs of the expression of TIMP1 by immunohistochemistry (IHC) in human lung cancer. Comparisons in (A) and (D) were done using Kruskal–Wallis one‐way analysis of variance followed by Dunn‐Bonferroni's test for multiple comparisons after samples proved not to follow a normal distribution using the Shapiro‐Wilk normality test (*p ≤ 0.05). Comparison in (C) was made using Wilcoxon test (*p ≤ 0.05).
FIGURE 4
FIGURE 4
High tumour expression of TIMP1 is associated with unfavorable prognosis. (A) Kaplan–Meier (KM) survival probability graph using TIMP1 mRNA expression in squamous cell carcinoma (left) and adenocarcinoma (right) from the PanCancer Atlas. (B) KM analysis of combined microarray databases from caBIG, GEO and TCGA repositories using TIMP1 as variable factor. (C and D) KM survival probability graph using TIMP1 relative proteomic expression level in lung cancer. Comparisons in A/B/C/D were made using the Log‐rank Mantel‐Cox test (*p ≤ 0.05).
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