Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Abstract

The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization

“…As MyD88 is widely expressed by different immune and nonimmune cells, emerging evidence has suggested that MyD88 plays different roles under different circumstances in different cells. Recently, it has been reported that MyD88 expression was crucial for progression to malignancy, with tumor-promoting functions both in intestinal epithelia and in myeloid cells (Holtorf et al, 2018). However, far less is known about the effects of MyD88 signaling-specific deficiency in myofibroblasts in a CAC mouse model.…”

Trial watch: TLR3 agonists in cancer therapy

“…[52][53][54][55][56][57] Of note, unlike other TLRs, TLR3 signaling appears to require tyrosine phosphorylation upon dsRNA recognition, 58 and operates exclusively via an MYD88 innate immune signal transduction adaptor (MYD88)-independent mechanism. 59,60 Defective TLR3 activity contributes to numerous pathologies, including chronic inflammation, sepsis, autoimmune disorders and cancer. [61][62][63][64][65][66] Specifically, loss-of-function TLR3 polymorphisms have been associated with an increased risk for breast carcinoma, 67 cervical cancer, 68 oral squamous cell carcinoma, 69 hepatocellular carcinoma (HCC), 70 and colorectal carcinoma (CRC); 71 as well as with poor disease outcome in patients with CRC 72 and non-small cell lung carcinoma (NSCLC).…”

“… 52 – 57 Of note, unlike other TLRs, TLR3 signaling appears to require tyrosine phosphorylation upon dsRNA recognition, 58 and operates exclusively via an MYD88 innate immune signal transduction adaptor (MYD88)-independent mechanism. 59 , 60 …”

BGN/TLR4/NF-κB Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells

“…All Toll-like receptors (TLRs) except TLR3 activate NF-κB signaling through the MyD88 pathway [3]. MyD88/TLR signaling is overexpressed and associated with intestinal tumor formation and progression [4].…”