Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246

Abstract

TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis.

Circulating microRNA‐1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma

“…Expression of miR‐1246 was thus found to promote invasiveness and stemness, and to be high in metastases . In addition to these findings, other results for cancer‐derived exosomes reinforce the argument that miR‐1246 is involved in tumor progression and metastasis, and has been proposed to serve as a biomarker for certain malignancies. Many reports have shown close associations between overexpression of circulating miR‐1246 and prognosis in several types of cancer, including non‐small‐cell lung prostate, colon, breast, pancreas, cervix, oral, and esophageal carcinomas …”

“…Distributions of the absolute expression level of each microRNA from the microarray are shown in Figure S1. In addition, recent studies have increasingly been reporting miR‐1246 as a promising biomarker for various cancers . Based on these reports and our findings, we next analyzed the level of miR‐1246 by real‐time qPCR.…”

Development of miRNA‐based therapeutic approaches for cancer patients

“…miRNA are also important for cell‐to‐cell communications involved in the inflammatory response, differentiation and tumor progression . miRNA are secreted from various types of cells through EV containing membrane proteins such as CD63, CD81 and CD9 .…”

Recent advances in understanding the complexities of metastasis

“…In addition, it is known that CAFs heavily influence cancer cell behaviour by inducing processes such as EMT to initiate their invasion 104– 107 or driving apoptosis to facilitate the switch between expansive invasion and CAF-led invasion 108 . Thus, the concept that tumours behave as communities 109 , in which cooperative behaviour occurs not only between cancer cell subclones but also between malignant and non-malignant cells 110 , adds significantly to the layers of complexity in treating these highly heterogeneous tumours. With this in mind, investigators are undertaking mathematical modelling to better understand the dynamics of cell–cell as well as cell–microenvironmental reciprocities that govern metastatic priming and progression 111– 114 .…”

“…Successful studies to date have shown that the escape of cancer cells from the primary tumour into the circulation can occur as both single cells or clusters of a few to a dozen strands or sheets 140– 143 ( Figure 1). What governs the spatial and temporal cues for cancer cell intravasation is still not fully elucidated, but evidence points toward intrinsic cancer cell cues, the activity of stromal cell populations such as macrophages 110, 144 , and organisation of the ECM. For example, cells may orientate according to ECM structures such as collagen fibres that then can direct tumour cell intravasation in in vitro breast cancer cells 145 .…”