N-(3-oxododecanoyl)-L-homoserine lactone interactions in the breast tumor microenvironment: Implications for breast cancer viability and proliferation in vitro

Abstract

It is well documented that the tumor microenvironment profoundly impacts the etiology and progression of breast cancer, yet the contribution of the resident microbiome within breast tissue remains poorly understood. Tumor microenvironmental conditions, such as hypoxia and dense tumor stroma, predispose progressive phenotypes and therapy resistance, however the role of bacteria in this interplay remains uncharacterized. We hypothesized that the effect of individual bacterial secreted molecules on breast cancer viability and proliferation would be modulated by these tumor-relevant stressors differentially for cells at varying stages of progression. To test this, we incubated human breast adenocarcinoma cells (MDA-MB-231, MCF-DCIS.com) and non-malignant breast epithelial cells (MCF-10A) with N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a quorum-sensing molecule from Pseudomonas aeruginosa that regulates bacterial stress responses. This molecule was selected because Pseudomonas was recently characterized as a significant fraction of the breast tissue microbiome and OdDHL is documented to impact mammalian cell viability. After OdDHL treatment, we demonstrated the greatest decrease in viability with the more malignant MDA-MB-231 cells and an intermediate MCF-DCIS.com (ductal carcinoma in situ) response. The responses were also culture condition (i.e. microenvironment) dependent. These results contrast the MCF-10A response, which demonstrated no change in viability in any culture condition. We further determined that the observed trends in breast cancer viability were due to modulation of proliferation for both cell types, as well as the induction of necrosis for MDA-MB-231 cells in all conditions. Our results provide evidence that bacterial quorum-sensing molecules interact with the host tissue environment to modulate breast cancer viability and proliferation, and that the effect of OdDHL is dependent on both cell type as well as microenvironment. Understanding the interactions between bacterial signaling molecules and the host tissue environment will allow for future studies that determine the contribution of bacteria to the onset, progression, and therapy response of breast cancer.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…For example, Akkermansia muciniphila , which confers metabolic benefits despite colonizing the gut in low abundances, restored sensitivity to immune checkpoint blockade (ICB) therapy in murine models and correlated with ICB therapeutic response in BC patients 10,11 . This field is in its infancy but it is believed that microbes may play a central role in cancer biology in several ways: (a) microbes and bacterial‐derived proteins directly regulate immune cell content and activation 12‐15 ; (b) microbes regulate metabolism of our diet (ie, fiber 16,17 ); (c) microbes alter estrogen bioavailability 18‐21 ; (d) bacterial‐derived quorum‐sensing proteins 12‐14 which are found in the mammary gland 22,23 ; and (e) microbes modify local or systemic levels of their own metabolites and host metabolites, such as short‐chain fatty acids or BAs 2 . With this examination of the most recent literature and trials, we implore the reader to consider how obesity, microbes, and metabolites derived from gut or extra‐intestinal depots impact tumor onset, progression, anti‐tumor immunity, and response to therapy.…”

Harnessing Tissue Engineering Tools to Interrogate Host-Microbiota Crosstalk in Cancer

“…Interestingly, breast tissue was identified as having the most diverse tumor microbiome with an average of 16.4 species per sample (Figures 1A-1C). In our own work, we previously examined the impact of molecules secreted by a bacterium that had been identified as present in the breast TME (Balhouse et al, 2017). This more recent finding by Nejman et al provides further evidence that local tumor microbiomes may play a critical role in multiple cancer types.…”

“…The secreted metabolites themselves may directly affect the tumor viability and proliferation. For example, we have previously shown that Pseudomonas aeruginosa found in breast cancer tissue secretes N-(3-oxododecanoyl)-L-homoserine lactone, which variably modulates viability of MDA-MB-231 and MCF-DCIS.com cells depending on the specific culture microenvironment (Balhouse et al, 2017).…”

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

“…The quorum sensing signal molecule, N-3-oxo-dodecanoyl-L-homoserine lactone (O-DDHSL) exhibited cytotoxic effect by inducing apoptosis, inhibiting colony formation, and reducing colony formation in pancreatic carcinoma cells [ 109 ]. O-DDHSL has also proved to mitigate proliferation and viability and induced significant necrosis in malignant MDA-MB-231 breast cancer cells [ 110 ]. Nandakumar et al synthesized various QS analogs and tested its activity on Hodgkin’s lymphoma cells.…”