Biology subjects

Devarajan, R.

Publications and source records attributed to Devarajan, R..

4 recordsLinked to original sources

bioRxiv2025

Complex I Drives Glutamine-Dependent TCA Cycle to Support Viability of MYChigh Breast Cancer Cells

In many cancers, stably elevated MYC levels drive persistent and concerted activation of cell growth promoting anabolic programs and the cell cycle in ways that are distinct from normal cells. Therefore, synthetic-lethal strategies to target MYC reprograming of these pathways may identify new selective anticancer therapies for the treatment of MYChigh tumors. Here, we identify enhanced mitochondrial respiration as a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH. Metabolic carbon tracing analysis revealed that MYC shifts TCA cycles carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors resulted in MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, persistent inhibition of tumor growth was achieved through combined inhibition of complex I and glutaminolysis. Our results suggest that the high respiration rate observed in MYChigh cells supports glutamine carbon-enriched TCA cycle, rendering MYChigh tumors selectively vulnerable to inhibitors of mitochondrial respiration and glutaminolysis.

cancer biology↗

bioRxiv2023

TEAD1 regulates ITGA1 and ITGA2 to control prostate cancer progression

The extracellular matrix (ECM) undergoes significant changes during prostate cancer (PCa) progression and actively regulates PCa growth and invasion. Here, we performed a meta-analysis of PCa cohorts and found that downregulation or loss of ITGA1 and ITGA2 integrin genes was associated with tumor progression to metastasis and poor prognosis in PCa patients. Genomic deletion of both 1- and 2-integrins activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT was induced by enhanced secretion and subsequent activation of autocrine TGF{beta}1 and nuclear targeting of YAP1. Our unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of 2- and 2-integrins in vitro and in vivo. Notably, clinical data analysis revealed that TEAD1 downregulation or loss was associated with aggressive PCa and could synergize with ITGA1 and ITGA2 expression to impact PCa prognosis and progression. Altogether, our results demonstrate that loss of 1- and 2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGF{beta}1-driven EMT.

cancer biology↗

bioRxiv2022

Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors

The tumor extracellular matrix (ECM) is a critical regulator of cancer progression and metastasis, significantly affecting the treatment response. Expression of collagen XVIII (ColXVIII), a ubiquitous component of basement membranes, is induced in many solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII is markedly upregulated in human breast cancer (BC) cells and is closely associated with a poor prognosis in high-grade BC, especially in human epidermal growth factor receptor 2 (HER2)-positive and basal/triple-negative cases. We identified a novel mechanism of action for ColXVIII as a modulator of epidermal growth factor receptor (EGFR/ErbB) signaling and show that it forms a complex with EGFR, HER2 and 6 integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/Akt cascades. In vivo studies with Col18a1 mouse models crossed with the MMTV-PyMT mammary carcinogenesis model showed that the short ColXVIII isoform promotes BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in both mouse and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII in human BC cells and the MMTV-PyMT model substantially improved the efficacy of certain EGFR/ERbB-targeting therapies, even abolishing resistance to EGFR/ErbB inhibitors in some cell lines. In summary, a new function is revealed for ColXVIII in sustaining the stemness properties of BC cells, and tumor progression and metastasis through EGFR/ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have significant therapeutic potential. One Sentence SummaryCollagen XVIII is upregulated in breast cancer and promotes mammary carcinogenesis through EGFR/ErbB signaling and by sustaining cancer stem cells, so that its targeting improves the efficacy of ErbB-targeted therapies.

cancer biology↗

bioRxiv2021

Disassembly of hemidesmosomes promotes tumorigenesis in PTEN-negative prostate cancer by targeting plectin into focal adhesions

Loss of 6{beta}4-dependent hemidesmosomes has been observed during prostate cancer progression. However, the significance and underlying mechanisms by which aberrant hemidesmosome assembly may modulate tumorigenesis remain elusive. Using an extensive CRISPR/Cas9-mediated genetic engineering approaches in different prostate cancer cell lines combined with in vivo tumorigenesis studies in mice, bone marrow-on-chip assays and bioinformatics, as well as histological analysis of prostate cancer patient cohorts, we demonstrated that simultaneous loss of PTEN and hemidesmosomes induced several tumorigenic properties including proliferation, migration, resistance to anoikis, apoptosis, and drug treatment in vitro, and increased metastatic capacity in vivo. Our studies showed that these effects were driven by activation of EGFR/PI3K/Akt and FAK/Src-pathways and were abolished by plectin downregulation. Therefore, dual loss of PTEN and hemidesmosomes may have diagnostic value helping to stratify prostate cancer patients with high risk for development of aggressive disease and highlight plectin as a potential therapeutic target in prostate cancer.

cancer biology↗