Role of the extracellular matrix-integrin interaction in enzalutamide resistance of bone metastatic castration-resistant prostate cancer

Bone metastatic castration-resistant prostate cancer (bone mCRPC) is the most prevalent type of prostate cancer metastasis, accounting for 90% of all metastasis incidence. Its resistance to androgen-deprivation therapy (ADT). Enzalutamide (Enz) is a second-generation androgen-receptor (AR) antagonist, developed to treat bone mCRPC by blocking the androgen signalling pathway. However, the emergence of resistance to Enz significantly limits therapeutic options for bone mCRPC patients. Although tumour-cell autonomous mechanisms are increasingly understood, roles played by the tumour microenvironment (TME) in driving Enz-resistance remain less clear. Previous has research revealed that macrophages, as a major TME component, are important in the development of Enz-resistance by modulating the extracellular matrix (ECM)-integrin signalling of cancer cells. However, more detailed mechanisms about how this signalling pathway contribute to the emergence of Enz-resistance are still limited. In this study, by using a novel in vivo murine bone metastatic prostate cancer model and in vitro assays, we investigated roles of the ECM-integrin signalling in the development of Enz-resistance. We first demonstrated that alter this signalling pathway in cancer cells can directly regulate their Enz-responsiveness. Various ECM and integrin proteins were significantly enriched in the TME of Enz-resistant tumours compared to naïve tumours. Promoting the ECM-integrin signalling pathway directly induced Enz-resistance in bone mCRPC, while its suppression significantly enhanced the response of cancer cells to Enz treatment. This can be achieved by modulating cancer cell proliferation and apoptosis. Furthermore, ECM-integrin signalling potentially affects the Enz-sensitivity by regulating the AR and its downstream signalling cascades in cancer cells. Next, we explored the relationship between the ECM-integrin signalling and immune cells within the TME. The TME of Enz-resistant bone metastatic tumours with overexpressed ECM and integrin genes from cancer cells exhibited increased infiltration of various immunosuppressive immune cells, particularly tumour-associated macrophages (TAMs). This was accompanied by decreased levels of pro-inflammatory immune cells. In contrast, tumours with downregulated ECM/integrin gene expression in cancer cells showed an opposite pattern in changes in immune cell infiltration, leading to a higher responsiveness to Enz treatment. Therefore, upregulated ECM-integrin signalling may create a more immunosuppressive tumour-promoting TME, which favors immune evasion of cancer cells, thus inducing Enz-resistance indirectly. Moreover, preliminary data suggest that small peptide fragments, matrikines, derived from degraded ECM proteins, may promote the differentiation and recruitment of immunoregulatory TAMs, thereby facilitating the development of Enz-resistance. Lastly, the bulk RNA-sequencing data using human prostate cancer cell lines suggested that targeting ECM-integrin signalling could be a promising therapeutic strategy for treating patients with Enz-resistant bone mCRPC. Collectively, our study highlights that the ECM-integrin signalling pathway contributes to the emergence of Enz-resistance and regulates immune responses in bone metastatic prostate cancer. Targeting ECM proteins and their integrin receptors may represent novel strategies, such as the development of new immunotherapies that could palliative, even reverse Enz-resistance in bone mCRPC, thus improving patient outcomes.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2024

Author dc:creator

• Zhang, Chengbin

Advisors dc:contributor.advisor

• Qian, Binzhi
• Yao, Chengcan

• Bone metastatic castration-resistant prostate cancer
• androgen-deprivation therapy
• Enzalutamide
• androgen-receptor
• second-generation androgen-receptor (AR) antagonist
• tumour microenvironment
• metastatic castration-resistant prostate cancer
• extracellular matrix
• extracellular matrix (ECM)-integrin signalling
• cancer cells
• signalling pathway
• tumour-associated macrophages
• human prostate cancer cell lines
• Enz-resistance

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/5374

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/42680