Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment

Abstract

SummaryROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

“…Characterization of the four cell populations via ELISA and cytokine array showed that some markers were shared, such as secretion of MCP1 (Fig EV1E and F), while others were more specific for M1A such as secretion of TNF‐α (Fig EV1C), MIG and RANTES (Fig EV1E, G, H) or M2, such as secretion of CCL22 (M2A) (Fig EV1D), IL‐10 and TGF‐β1 (M2D/A) (Fig EV1E, I, J) (). With regard to expression markers known to be induced by certain stimuli (Georgouli et al , ) (and associated with certain macrophage subgroups), we observed by FACS analysis that the majority of the cells in the four populations were double‐positive for HLA‐DR/CD86 (Fig EV2A and B), with M1D/A expressing HLA‐DR at higher level than M2A/D (Fig EV2C), while CD86 was higher in M1A and M2A than in M1D and M2D (Fig EV2D). The percentage of cells double positive for CD206/CD163 was higher in the M2D/A populations (Fig EV2E and F), and CD206 was expressed at higher level by M1D and M2A, while CD163 by M2D/A (Fig EV2G and H).…”

“…Macrophages were stained as previously described (Georgouli et al , ). Macrophages were washed three times with PBS −/− , incubated for 5 min at 37° in PBS −/− and then gently scraped and washed once with FACS buffer (PBS −/− , 1% BSA, 2 mM EDTA, 0.1% NaN 3 ).…”

Targeting Aryl Hydrocarbon Receptor with small molecule, 1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester blocked human glioma cell invasion via MYH9

“…The reason for the lack of A1 mode in ITE treated group needs further investigation. Moreover, MYH9 promotes tumor progression by modulating the immune micro-environment, so reduced MYH9 level by ITE treatment potentially offers immune-promoting benefit in addition to its invasion-inhibiting effects [26]. When writing this paper, it is reported that Programmed death-ligand1 (PDL1)/Programmed cell death protein 1(PD1) blockade was effective as neoadjuvant therapy in GBM.…”

Profiles and clinical significance of immune cell infiltration in pancreatic adenocarcinoma

“…As well all known, immune cells infiltrating in the tumor microenvironment have been uncovered to play prominent roles in the biological behaviors of various cancers [14-16]. It has been revealed that identifying subtypes of the immune microenvironment in PAAD provides the promising opportunities for therapeutic development based on personalization of systemic immunotherapies [17].…”