HER2鈭�16 is an oncogenic variant of the human epidermal growth factor receptor (HER2); it is implicated in breast cancers and other types of tumors as a motor for tumorigenesis and the metastatic process. The laboratory of Professor William Muller, from the Rosalind and Morris Goodman Cancer Institute of 平特五不中, collaborated with Professor Philippe Roux, Director of the Cell Signaling and Proteomics Research Unit at IRIC, to characterize the molecular mechanisms underlying HER2螖16-mediated oncogenicity.
The results obtained suggest that HER2螖16 alters the tumor microenvironment via the ENPP1 protein, which could prove to be an interesting therapeutic target. Published in the journal听Cancer Immunology Research, the study was conducted jointly by听Sherif Samer Attalla, doctoral student in the Muller laboratory, and Jonathan Boucher, postdoctoral fellow in the Roux laboratory. The labs of Morag Park and Logan Walsh at the GCI also participated in this study.
Tumors expressing HER2螖16 are cold, or non-immunogenic
To investigate the roles of HER2 variants in the regulation of the tumor microenvironment, new transgenic mouse lines expressing HER2 or its HER2螖16 variant in mammary epithelium were generated. HER2螖16 tumors derived from this mouse model were found to be cold: infiltration by immune cells is reduced, activation of inflammatory signaling pathways is reduced and expression of immunomodulatory cytokines is altered. The HER2螖16 variant therefore alters the tumor microenvironment, making it less conducive to an anti-tumor immune response.
Increasing ENPP1 levels to reduce immune response
Using a proteomic approach, the team then identified the ENPP1 protein as being more present on the surface of cells expressing the HER2螖16 variant. Enzymatic assays revealed that ENPP1 downregulates immune-activating cytokines while upregulating those with immunosuppressive properties, leading to the cold tumor microenvironment phenotype. Suppression of ENPP1 in HER2螖16 tumors reduces tumor growth; moreover, this reduction is accompanied by an increase in the immune infiltration of the tumor.
In sum, this work has identified the surface protein ENPP1 as being responsible for the reduced immune infiltration observed in tumors expressing HER2螖16. ENPP1 therefore represents an interesting new therapeutic target: its inhibition could increase the antitumor immune response in HER+ breast cancer patients.
Sherif Samer Attalla, Jonathan Boucher, Hailey Proud, Tarek Taifour, Dongmei Zuo, Virginie Sanguin-Gendreau, Chen Ling, Gabriella Johnson, Vincent Li, Robin B. Luo, Hellen Kuasne, Vasilios Papavasiliou, Logan A. Walsh, Mark Barok, Heikki Joensuu, Morag Park, Philippe P. Roux and William J. Muller.听.听Cancer Immunology Research. 2023
Adapted from听