DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

Abstract

The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR / IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.

Euphorbia factor L1 suppresses breast cancer liver metastasis via DDR1-mediated immune infiltration

“…DDR1 depletion inhibits cell growth and cell cycle progression and enhances the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib in estrogen receptor (ER)-positive, HER2-negative breast cancer [ 33 ]. Vella et al observed that DDR1 influences metabolic reprogramming in breast cancer cells by cross-talking to the Insulin/IGF system [ 34 ]. In addition, tumor DDR1 promotes collagen fiber alignment and contributes to breast cancer development by instigating immune exclusion [ 9 ].…”

The profile of receptor protein tyrosine kinases (RPTKs): taking AXL and DDR as examples

“…In addition, collagen I induces the secretory pathway-derived calcium-transporting ATPase to facilitate breast cancer cell proliferation, increasing DDR1 expression in breast cancer. [22] Collagen binding has also been increased in the ECM by the extracellular domain of DDR1, leading to tighter collagen fibrils and preventing immune cell infiltration. In other words, collagen cells are intimately involved in the migration, proliferation and defence of breast cancer.…”

Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications

“…The IR-A/IGF2 contributes to BC metabolic reprogramming. Vella et al [12] now show that in BC cells overexpressing IGF2, DDR1 depletion caused reduction of ATP production by approximately 50% affecting both glycolysis and mitochondrial activity. Similar effects were observed in BC cells overexpressing the IR-A and stimulated with either insulin or IGF2.…”

“…In fact, the blockade of the IGF1R was promising in preclinical studies but has yielded disappointing results in the clinical setting [11]. The paper by Vella et al [12] aimed at exploring the possibility that targeting DDR1, a non-integrin collagen receptor with tyrosine-kinase activity, could work as novel approach in human breast cancer (BC) therapy. The authors evaluated whether DDR1 targeting could reverse the metabolic reprogramming induced by the activation of insulin/IGF signaling.…”

“…However, DDR1 silencing also reduced BC cell bioenergetics in the absence of insulin or IGF2. Vella and associates [12] conclude that, as no specific pharmacological tools are currently available to specifically target the IGF2/IR-A, targeting DDR1 would have the added benefit of offsetting the pro-tumorigenic effects of Insulin/IGF2, which include a reversion of insulin/IGF2-dependent metabolic reprogramming.…”