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Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes

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Abstract

Metabolic dysregulations have been identified as intrinsic hallmarks of cancer cells. Investigations of altered metabolic processes, in the context of the associated oncogenic signaling pathways are expected to pave way for the development of targeted cancer therapeutics. We have recently identified the enrichment of glucose and glutamine metabolism in a subset of intestinal subtype gastric tumors at the level of expression of genes, gene sets and the occurrence of metabolites. On the other hand, glucose transport, glucan and fatty acid metabolism were enriched in a subset of diffuse subtype gastric tumors. In the current study, along with glucose metabolism, mTOR, HSP90, MYC, E2F, P53 and proteasome pathways were found enriched in a subset of intestinal subtype and a part of MSI subtype gastric tumors. On the other hand, along with fatty acid metabolism, the oncogenic pathway KRAS was found to be enriched in a subset of GS tumors among diffuse subtype gastric tumors. Thus, oncogenic signaling pathways associated with two distinct metabolic rewiring which differentially occurs between major gastric cancer subtypes were identified. These pathways seem the potential targets to differentially target these gastric cancer subtypes. Exploratory integrative genomic analyses reveal HSP90 inhibitors, AKT/mTOR inhibitors, and cell cycle inhibitors as potential agents to target the gastric tumors with the rewired glucose metabolism and MEK/MAPK inhibitors as suitable drug candidates to target the diffuse subtype tumors with the dysregulated fatty acid metabolism. This observation would pave way for the selective and targeted use of signaling pathway modulators for targeted and stratified gastric cancer therapeutics.

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Data Availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

We thank Council of Scientific and Industrial Research (CSIR), Govt. of India for NET-SRF fellowship support to Karthik Balakrishnan. UGC-CEGS, UGC-NRCBS, UGC-CAS, DBT-IPLS, DST-FIST, MKU-RUSA, and DST-PURSE program supported central facilities of School of Biological Sciences, Madurai Kamaraj University are acknowledged.

Funding

This work was supported by the Department of Biotechnology (DBT), Government of India, the Unit of Excellence (UOE) in Cancer Genetics grant BT/MED/30/SP11290/2015 and MKU-RUSA 2020/Genomic Subtype grant to Dr. Kumaresan Ganesan, Madurai Kamaraj University.

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  1. Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, Tamil Nadu, India

    Karthik Balakrishnan & Kumaresan Ganesan

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  1. Karthik Balakrishnan
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  2. Kumaresan Ganesan
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Contributions

KB and KG conceived and designed the experiments and wrote the paper. KB performed the experiments and, KB and KG analyzed the data. KG also contributed the materials.

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Correspondence to Kumaresan Ganesan.

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Balakrishnan, K., Ganesan, K. Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes. Med Oncol 39, 132 (2022). https://doi.org/10.1007/s12032-022-01717-9

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