Biological relevance of an interferon signature induced by Insulin receptor isoform A in breast cancer

The oncofetal isoform of the insulin receptor (IR-A) is often overexpressed in various cancer histotypes including breast cancer (BC). The IR-A contributes to cancer progression by mediating the effects of hyperinsulinemia in obese insulin-resistant patients and regulating paracrine/autocrine IGF2 action. We have preliminary evidence that in the absence of its cognate ligands IR-A overexpression is specifically associated with the expression of several type I interferon(IFN)-stimulated genes (ISGs) including OAS3, IFI35, IFT1 and genes encoding for ligands of immune cells inhibitory receptors such as PD-L1 and Lgals3bp. Moreover, a feed-forward crosstalk of IR-A with the collagen receptor DDR1 further potentiates the expression of these genes. Hypothesis: We will test the hypothesis that IR-A overexpression may specifically trigger a molecular switch associated with the expression of genes implicated in type I IFN response and innate immunity that might favor BC immunoescape and resistance to therapy. We further propose that inhibition of the IR-A/DDR1 signaling platform might be a strong candidate for targeting this gene signature especially in the context of hyperinsulinemia.

Aims: We intend to: 1) Characterize the IR-A-associated ISG signature and elucidate its regulatory mechanisms; 2) Assess and target the biological function of IR-A-regulated ISG signature in preclinical models; 3) Evaluate the clinical relevance of IR-A associated ISG signature in BC patients.

Experimental Design: Using both transcriptome and proteomics data, we will first investigate whether IR-A overexpression is associated with a unique ISG signature. To assess specificity for IR-A, we will use BC cells KO or silenced for the endogenous IR or the homologousIGF1R and engineered to express either IR-A, IR-B or IGF1R. We will then investigate the molecular mechanisms leading to IR-A-dependent ISGs transcription especially in the context of hyperinsulinemia and obesity. We will next assess the relevance of this ISG signature in BC cell proliferation, invasion and maintenance of stem-like phenotype, as well as its contribution to resistance to chemotherapeutic drugs and anti-PD-L1 antibodies. In particular, we will perform in silico gene-centric pathway analysis to determine all druggable targets and discover the best combination therapies that will be evaluated in various models including organoids and mice xenografts with BC cells overexpressing IR-A. The clinical relevance of this pathway to human BC in obese patients will be investigated by RNA-seq of BC specimens followed by bioinformatics analysis, and findings will be corroborated with data from publicly available databases.

Expected Results: We expect to establish that overexpression of the oncofetal IR-A in BC drives a novel molecular switch involved in immunoescape and tumor metastases, and therapy resistance. By combining experimental and bioinformatics approaches we also expect to identify critical druggable nodes of this molecular signature allowing to overcome cancer metastases and resistance to therapies especially in obese, hyperinsulinemic patients. Impact on Cancer: Aging and post-menopausal status favor the occurrence of obesity and insulin resistance both of which are known to impact negatively on BC outcome. The results of these studies will provide a paradigm shift for the identification of novel biomarkers and treatments for a personalized therapy of advanced BC in the context of obesity and insulin resistance.