Purwin, T. J. | bioRxiv Science

bioRxiv2024

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Uveal melanoma (UM) can remain in clinical dormancy for decades only to later produce lethal metastases. Using Gq/11mut/BAP1wt UM xenograft models and human metastatic samples, we identified NR2F1 as a key inducer of UM disseminated cancer cell (DCC) dormancy. Dormant UM DCCs upregulate NR2F1, neural crest genes and, along with suppression of proliferation programs, NR2F1 silences YAP1/TEAD1 transcription by altering histone H3 activation marks. YAP1 can reciprocally repress NR2F1, but inhibiting Gq/11 signaling or activating NR2F1 can arrest UM growth. NR2F1 knockout led to dormant DCC awakening and liver metastatic growth. NR2F1 and YAP1 inverse expression was confirmed in human livers carrying UM solitary, small DCC clusters as well as large metastases. Intriguingly, RNA-seq and Cut&Run analysis revealed that NR2F1 short-circuits oncogene signaling by repressing multiple G-protein signaling components. Our work provides previously unrecognized mechanistic insight into UM DCC dormancy and potential pathways for interception. Statement of significanceNR2F1 epigenetically suppresses genes associated with G-protein signaling, cell cycle, and YAP1/TEAD1 pathways, inducing dormancy in uveal melanoma (UM) disseminated cancer cells. This study unveils novel markers for UM dormancy and reactivation, positioning NR2F1 as a promising target for intercepting residual and UM metastatic disease.

cancer biology↗

bioRxiv2019

Murine cytomegalovirus infection of melanoma lesions delays tumor growth by recruiting and re-polarizing monocytic phagocytes in the tumor

Cytomegalovirus (CMV) is a ubiquitous {beta}-herpesvirus that infects many different cell types. CMV has been found in several solid tumors and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, CMV infection delays tumor growth. We previously showed that wild-type murine (M)CMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here we show that MCMV delayed the growth of these immunologically \"cold\" tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward an M1-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the anti-tumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically \"cold\" tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses.\n\nImportanceCytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine (M)CMV delayed tumor growth and activated tumor-specific immunity, although the mechanism was unclear. We now show that MCMV delayed tumor growth not by infecting and killing tumor cells, but rather by recruiting macrophages to the tumor. A viral chemokine was necessary to recruit macrophages and delay tumor growth. Furthermore, MCMV infection altered the functional state of the macrophages. Finally, we found that repeated MCMV injections sustained the anti-tumor effect suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting and infecting macrophages in the tumor.

immunology↗