Deregulated glutamate to pro-collagen conversion is associated with adverse outcome in lung cancer and may be targeted by renin-angiotensin-aldosterone system (RAS) inhibition

Abstract

Background:The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC. Methods: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis. Results: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids. Conclusion:We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.

SHetA2 Attack on Mortalin and Colleagues in Cancer Therapy and Prevention

“…Currently, this is the only report of mortalin directly binding to these specific proteins. Overexpression of ALDH18A1 in cancer supports accelerated metabolism, angiogenesis, metastases and chemotherapy resistance ( Tang et al, 2018 ; Ding et al, 2020 ; Guo et al, 2020 ; Rohlenova et al, 2020 ; Shenoy et al, 2020 ; Kocher et al, 2021 ). Complexes of CTPS1 and inosine monophosphate dehydrogenase type 2 (IMPDH2), called cytoophidia or rods and rings, regulate key steps in CTP and GTP biosynthesis.…”

COL3A1 Overexpression Associates with Poor Prognosis and Cisplatin Resistance in Lung Cancer

“…The close implication of the collagen family in tumorigenesis has been well documented. 19 , 20 , 21 , 22 , 23 , 24 For example, collagen prolyl 3-hydroxylation (P3H) was shown to have low expression in lung cancer, whereas its overexpression suppressed cancer cell growth, migration, and invasion, and it had pro-apoptotic roles in lung cancer. 25 As expected, COL3A1 has vital roles in carcinogenesis, where it serves as an oncogene.…”

Identification of Key Genes and Potential Pathways Associated with Mastitis Induced by E. coli

“…The results of a study on the identification of candidate genes affecting mastitis in cows showed that ALDH18A1 was among DEGs in mammary tissue after intramammary infection with E. coli or Streptococcus uberis (Chen et al 2015 ). ALDH18A1 is one of the genes in the collagen synthesis pathway (Kocher et al 2021 ). Therefore, ALDH18A1 can be considered an important gene in mastitis induced by E. coli .…”