TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response

Abstract

Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems. Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations. Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses. Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.

Identifying cell type-specific transcription factor-mediated activity immune modules reveal implications for immunotherapy and molecular classification of pan-cancer

“…Kim et al . [ 37 ] have demonstrated that TRIB1 regulates tumor growth and is associated with breast cancer survival and treatment response. In addition, BACH2 also directly regulates TF XBP1, which can reduce the proliferation and stemness of cancer cells [ 38 ].…”

Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

“…We identified 80 sgRNAs that meet one (65), two (17) or all (2) of these criteria (Supplementary Table 3). Among the genes targeted by these sgRNAs are those involved in cell motility (Tesk1, Pkn1 and Mylk4) [20][21][22] , nucleotide homeostasis and metabolism (Prps1, Prps2, Adck2 and Nme8) 23 or modulation of insulin sensing (Trib1 and Pip4k2c) [24][25][26] or function as tumor suppressors (Fgfr3) 27 , such that the loss of these genes would promote hallmarks of metastasis. The top hit in this screen by all applied metrics was loss of Pip4k2c, which encodes phosphatidylinositol-5-phosphate 4-kinase type 2 gamma.…”

“Oh, Dear We Are in Tribble”: An Overview of the Oncogenic Functions of Tribbles 1

“…TRIB1 reduces DR5 protein levels in breast cancer cells through its elevated NF-кB signaling, thus decreasing TRAIL-induced apoptosis [36]. Heightened expression of TRIB1 in tumor associated macrophages (TAMs) influences the breast cancer tumor microenvironment by regulating oncogenic cytokine expression [73].…”

“…In primary GBM cells, TRIB1 causes upregulation of the ERK and Akt pathways and modulation of p53 function through COP1 and HDAC1, further contributing to therapy resistance [34]. TRIB1 negatively regulates the anti-tumor cytokine IL-15 in TAMs in breast tumors, causing a decrease in T-cells that promote anti-tumor responses [73]. TRIB1 has been identified as a negative regulator of T-cell receptor (TCR) signaling via its interaction with MALT1, a TCR activator, leading to disruption of MALT1 signaling complexes responsible for optimal T cell activation and function [49].…”