Edinburgh Cancer Research

Kindlin-1 modulates the immune environment in breast cancer

Our scientists identify a novel function for Kindlin-1 in regulation of anti-tumour immunity.

Loss of Kindlin-1 leads to altered cytokine secretion [for details see Webb ER et al. Elife. 2023;12:e85739].
Loss of Kindlin-1 leads to altered cytokine secretion [for details see Webb ER et al. Elife. 2023;12:e85739].

Kindler syndrome is a rare type of epidermolysis bullosa, which is a group of genetic conditions that cause the skin to be very fragile and to blister easily. It is associated with loss-of-function mutations in the gene FERMT1 that codes for the protein Kindlin-1. Kindlin-1 is thought to be active in the interactions between cytoskeleton (a structure that helps cells maintain their shape and internal organization) and the extracellular matrix (an intricate network of molecules helping to maintain tissue structure), through its ability to bind to cell adhesion molecules known as beta-integrins. Kindlin-1 is also believed to have other functions and has been implicated in cancer. Studies have identified an important pro-tumourigenic role for Kindlin-1 in breast cancer, where it promotes cell migration, adhesion and so called epithelial-mesenchymal transition (a process enabling epithelial cells to acquire more migratory mesenchymal cell phenotype). It is also associated with increased lung metastasis and lung metastasis-free survival. Unfortunately, the mechanisms involved remain poorly understood.

In order to study roles of Kindlin-1 in breast cancer, Edinburgh Cancer Research investigators at the Institute of Genetics and Cancer used mice models in which functions of Kindlin-1 could be analysed. In one of these models, Met-1 murine breast cancer cells had been engineered to produce cell populations that were either devoid of Kindlin-1, expressed normal Kindlin-1 or expressed a mutated version of Kindlin-1 unable to bind to integrins. These cells were subsequently grown as tumour grafts in mice. The other model employed mammary tumour formation driven by expression of polyoma virus middle T (PyV-mT) oncogene. PyV-mT oncogene induces tumours in mice by mimicking an activated growth factor receptor. Our investigators used specially designed mice strains that produced PyV-mT oncogene in the presence or absence of Kindlin-1.

Analysis of tumour formation and tumour microenvironment in these models demonstrated that Kindlin-1 is involved in regulation of anti-tumour immunity. The researchers showed that Kindlin-1 dependent secretion of cytokines (small proteins that are crucial in controlling the growth and activity of immune system cells and blood cells), such as Interleukin 6 (IL6), can impact the tumour immune environment by modulating tumour associated T cell populations (T cells are immune cells that control tumour growth). Interestingly, this newly identified function of Kindlin-1 might not be dependent on its ability to bind to integrins.

The study was driven by Dr Emily Webb and supervised by Prof Val Brunton. It has been published by the journal Elife in the article titled “Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models”. The work was supported by funding from Cancer Research UK.

Our study provides novel mechanistic insights into how Kindlin-1-expressing tumours can evade immune destruction. As Kindlin-1 is upregulated in breast cancer and linked to survival, targeting Kindlin-1-dependent pathways linked to immune phenotypes may provide a novel strategy to increase the efficacy of immunotherapies in breast cancer, particularly methods relating to reinvigorating the anti-tumour T cell response. Of course, the relevance of our findings to human cancer needs further validation.

Dr Emily Webb and Prof Valerie BruntonUniversity of Edinburgh

Related Links

Article in Elife: https://elifesciences.org/articles/85739

Professor Val Brunton Group website: https://www.ed.ac.uk/cancer-centre/research/brunton-group

Information about breast cancer: https://www.cancerresearchuk.org/about-cancer/breast-cancer

Related Stories