Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model

Our plain-English summary of Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model, by S. Borchert, A. Mathilakathu, A. Nath, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: S. Borchert, A. Mathilakathu, A. Nath, M. Wessolly, E. Mairinger, D. Kreidt, J. Steinborn, R.F.H. Walter, D.C. Christoph, J. Kollmeier, J. Wohlschlaeger, T. Mairinger, L. Brcic, F.D. Mairinger
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(15)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the "conditional inference tree" (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies.

In plain English

This retrospective study examined stored tumor tissue from 77 pleural mesothelioma patients treated in Germany between 2002 and 2009. Asbestos exposure was not studied. The authors graded the scar-like reaction around the tumor (desmoplastic stromal reaction, DSR), stained for fibroblast activation protein (FAP), and measured expression of 76 genes. DSR appeared in 52 of 77 samples, 17 graded DSR-high. Higher FAP gene expression was linked to DSR (p = 0.025); FAP staining was not (p = 0.23). Presence or amount of DSR was not significantly linked to overall survival. However, median survival was 29.2 months (95% CI 17.1 to 44.2) with DSR-high tumors, versus 15.9 (13.8 to 27.3) without DSR and 15.8 (11.4 to 24.4) with low DSR, a significant difference between DSR-high and the other groups (p = 0.044). Higher expression of MYT1, KDR, PIK3R1, PIK3R4 and SOS1 was associated with shorter survival. Higher expression of VEGFC, FAP and CDK4 was associated with longer survival. The authors concluded that cancer-associated fibroblasts and related genes are important for predicting survival. They noted a limited gene panel, a small sample, and need for laboratory validation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of archived tumor tissue: microscopic grading, immunohistochemistry, digital gene expression analysis and a machine learning (decision-tree) survival analysis
• Who was studied: 77 patients with pleural mesothelioma (62 epithelioid, 8 biphasic, 7 sarcomatoid; 64 men, 13 women) treated in Essen (2006 to 2009) or Berlin (2002 to 2009), Germany. Overall survival was available for 73 patients and progression-free survival for 34.
• Exposure: Asbestos exposure was not studied; asbestos is mentioned only as background in the introduction. The factors studied were the tumor stromal reaction (DSR), FAP staining, and RNA expression of a 76-gene panel covering cell signaling, growth factors and cancer-associated fibroblast markers.
• Main results:
  • DSR was seen in 52 of 77 samples (67.5%). 35 of 77 (45.5%) were graded DSR-low and 17 of 77 (22.1%) DSR-high.
  • Higher FAP gene expression was significantly associated with the appearance of DSR (p = 0.025).
  • FAP immunohistochemistry was not significantly associated with DSR (p = 0.23).
  • Neither the appearance of DSR, its amount, nor FAP staining was significantly associated with overall survival.
  • Median survival was 29.2 months (95% CI 17.1 to 44.2) for patients with DSR-high samples, compared with 15.9 months (95% CI 13.8 to 27.3) for those without DSR and 15.8 months (95% CI 11.4 to 24.4) for those with low DSR.
  • The survival difference between DSR-high samples and the other groups was statistically significant (p = 0.044; HR 1.75; 95% CI 1.02 to 3.00).
  • For progression-free survival, DSR-high samples did not differ significantly from the other two groups (p = 0.424).
  • Higher expression of MYT1, KDR, PIK3R1, PIK3R4 and SOS1 was associated with shorter overall survival. Higher expression of VEGFC, FAP and CDK4 was associated with longer overall survival.
  • Median overall survival was 18.7 months for the high FAP expression group (n = 46) versus 16.0 months for the low expression group (n = 27) (p = 0.012; HR 1.93; 95% CI 1.15 to 3.24).
  • Higher PIK3C3 and CDKN1B expression was associated with shorter progression-free survival. Higher NRAS expression was associated with longer progression-free survival.
  • The decision-tree (machine learning) analysis of overall survival produced a three-tier grouping based on FAP, NF1 and RPTOR expression.
• The authors' conclusion: The authors concluded that cancer-associated fibroblasts and their related genes are important for predicting overall and progression-free survival in pleural mesothelioma.
• Limitations the authors state:
  • The limited gene panel does not cover all signaling in the tumor environment.
  • The hypothesis-driven choice of genes may be more error-prone than a supervised approach.
  • Only gene expression was measured, not actual protein amounts.
  • The sample size is small.
  • Bulk RNA analysis cannot assign gene expression to specific cell types.
  • Laboratory (functional) validation of the findings is still needed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Fibroblast, Pleural Mesothelioma, Desmoplastic Mesothelioma, Tumor Microenvironment, Immunohistochemistry, Median Overall Survival, Biomarker.

Related studies

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• BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients — M. De Marco, N. Del Papa, et al. (2022)
• Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro — S. Borchert, M. Wessolly, et al. (2019)
• Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning — Y. Xiao, W. Huang, et al. (2022)
• Cancer-Associated Fibroblasts Regulate Kinase Activity in Mesothelioma Cell Lines via Paracrine Signaling and Thereby Dictate Cell Faith and Behavior — A. Mathilakathu, M. Wessolly, et al. (2022)
• The use of a next-generation sequencing-derived machine-learning risk-prediction model (OncoCast-MPM) for malignant pleural mesothelioma: a retrospective study — M.G. Zauderer, A. Martin, et al. (2021)

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