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PI3K/AKT/mTOR inhibitors as potential extracellular matrix modulators for targeting EMT subtype gastric tumors

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Abstract

Targeting the extracellular matrix (ECM) is considered as a promising strategy in cancer therapeutics. This study was designed to identify the potential ECM modulators for gastric cancer therapeutics. Exploration of the expression profiles of gastric tumors revealed the elevated expression of ECM genes in gastric tumor tissues compared to the adjacent normal tissues with increased expression in diffuse subtype gastric tumors and specifically in epithelial to mesenchymal transition (EMT) molecular subtype tumors. Consensus ECM gene set was derived from the expression profiles of gastric tumors. The correlative analysis was performed between the expression pattern of the ECM gene set and the drug sensitivity pattern of a panel of drugs across gastric cancer cell lines. Negative correlation between the expression of ECM genes and sensitivity of a number of drugs targeting PI3K/mTOR signaling, chromatin histone acetylation and ABL signaling was observed. These pathways are known for their role in cell-mediated adhesion, differentiation and epithelial to mesenchymal transition. The current results reveal the possibility of using PI3K/AKT/mTOR modulators for targeted gastric cancer therapy in patients with dysregulated ECM.

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Abbreviations

ACRG:

Asian Cancer Research Group

ATCC:

American Type Culture Collection

CCLE:

The cancer cell line encyclopedia

ECM:

Extracellular matrix

EMT:

Epithelial to mesenchymal transition

GDSC:

Genomics of drug sensitivity in cancer

GEO:

Gene expression omnibus

MMP:

Matrix metalloproteinase

MSigDB:

Molecular signatures database

TCGA:

The cancer genome atlas

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Funding

This work was supported by the Department of Biotechnology (DBT), Government of India, through the Unit of Excellence (UOE) in Cancer Genetics Grant BT/MED/30/SP11290/2015 and MKU-RUSA supported grant 014/ RUSA/MKU/2020-2021 to Dr. Kumaresan Ganesan, Madurai Kamaraj University. Senior Research Fellowship to Ponmathi Panneerpandian from Lady Tata Memorial Trust, Mumbai, India, is acknowledged. MKU-RUSA, DST-FIST, UGC-NRCBS, UGC-CAS, and DST-PURSE programe supported central facilities of SBS, MKU are acknowledged.

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Authors and Affiliations

  1. Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India

    Ponmathi Panneerpandian & Kumaresan Ganesan

Authors
  1. Ponmathi Panneerpandian
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  2. Kumaresan Ganesan
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Contributions

GK and PP conceptualized the study. PP performed the experiments. GK and PP wrote the paper. PP and GK analyzed and interpreted the data.

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Correspondence to Kumaresan Ganesan.

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Supplementary Fig. S1

: Extracellular matrix gene sets are highly expressed in gastric tumors. A Heatmap showing differential expression of ECM gene sets across the gastric tumor profiles GSE29272 (A) and GSE54129 (B) containing normal and gastric tumor samples. The ECM genes are highly expressed in gastric tumors compared to the normal tissues. B Pathway activation scoring for the 21 ECM gene sets across the gastric tumor profiles GSE3809 (C), GSE62254 (D) and TCGA (E) reveal the enrichment of ECM gene sets in diffuse subtype gastric tumors compared to intestinal subtype gastric tumors. The derived 141 ECM genes obtained through overlap among 21 ECM gene sets show the higher expression of ECM genes in diffuse subtype gastric tumors in the gastric tumor profiles GSE62254 (F), GSE35809 (G), GSE22377 (H), and TCGA (I). For the clear visibility of the ECM gene sets comprising a list of 21 signatures is provided in Supplementary Table S1. Fig. S2: The table represents the previously annotated drug probabilities for diffuse, epithelial to mesenchymal transition, and genomically stable subtypes of gastric cancers for TCGA and ACRG cohort based studies. Fig. S3: Analysis of the potential ECM targetable drugs. A Expression of ECM genes across a panel of gastric cancer cell lines. B, C The sensitivity pattern of the corresponding gastric cancer cell lines to dactolisib,the PI3K inhibitor (B) and dasatinib—an ABL inhibitor (C), show striking negative correlation. D The genes downregulated upon treatment with dasatinib also overlap with the signatures associated with EGFR and vasculature from MsigDB indicating its potential role in inhibiting angiogenesis. E Gene ontology based functional analysis of the genes downregulated by dasatinib show the enrichment of TGF-β gene set. (PPTX 1801 kb)

Supplementary Table S1

: List of ECM related signatures collected from MSigDB and used for pathway activation scoring in gastric tumors. Table S2: ECM gene list (n = 141) derived by overlap among the collected 21 ECM related gene sets. Table S3: The drugs negatively correlated for their expression of ECM with sensitivity to drugs belonging to the annotated target pathways along with their respective correlation coefficient values. (XLSX 58 kb)

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Panneerpandian, P., Ganesan, K. PI3K/AKT/mTOR inhibitors as potential extracellular matrix modulators for targeting EMT subtype gastric tumors. Med Oncol 40, 120 (2023). https://doi.org/10.1007/s12032-023-01984-0

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