Guljar, N. | Search bioRxiv

bioRxiv2022

Proteomic profiling identifies co-regulated expression of splicing factors as a characteristic feature of intravenous leiomyomatosis

Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbours unique genomic and transcriptomic alterations when compared to uterine leiomyoma (uLM), which may account for their distinct clinical behaviour. Here we undertake the first comparative proteomic analysis of IVLM and other smooth muscle tumours (comprising uLM, soft tissue leiomyoma and benign metastasising leiomyoma) utilising data-independent acquisition mass spectrometry. We show that, at the protein level, IVLM is defined by the unique co-regulated expression of splicing factors. In particular, IVLM is enriched in two clusters composed of co-regulated proteins from the hnRNP, LSm, SR and Sm classes of the spliceosome complex. One of these clusters (Cluster 3) is associated with key biological processes including nascent protein translocation and cell signalling by small GTPases. Taken together, our study provides evidence of co-regulated expression of splicing factors in IVLM compared to other smooth muscle tumours which suggests a possible role for alternative splicing in the pathogenesis of IVLM.

cancer biology↗

bioRxiv2019

Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

Under normal conditions, the immune system is capable of rapidly detecting and eliminating potentially dangerous entities, including tumor cells. Due to intense selection pressure imposed by the immune response, tumor cells often evolve strategies to avoid elimination in a process known as immunoediting. It is less known how the evolutionary response to immune predation is altered by context. We explore the evolution of immune escape strategies in ductal cancers, a natural case in which to study evolution in different contexts: inside and outside of ducts. We highlight the role of macrophages as a source of \"public goods,\" releasing diffusible factors (reactive oxygen species and growth factors). Immunohistochemistry reveals differences between macrophage densities of invasive ductal carcinomas and non-invasive ductal carcinomas in situ. For the first time, immunohistochemistry (IHC) imaging data comparing DCIS to IDC were used to initialize mechanistic agent-based models of evolutionary dynamics. By using IHC to map the initial conditions of a growing tumor, we show that spatial competition and structure influence transient dynamics during invasion. These dynamics are context-dependent, a conclusion that may be missed from interpreting imaging or non-spatial modeling alone. Before invasion, the presence of macrophages correlate with shorter ductal breach times. After invasion, tumors may employ a \"pioneer-engineer\" strategy where pioneering immunoresistant cells on the tumors edge stimulate the release of M1-macrophage-derived reactive oxygen species, degrading surrounding stroma. Behind the invasive edge, the engineering immunosuppressive cells promote the release of M2-macrophage-derived growth factors, providing a long-term immune escape strategy. Together, mathematical modeling and image analysis highlight the crucial role tumor-associated macrophages play in immune escape and invasion, both inside and outside of ducts.

cancer biology↗