Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples. 

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Deep Visual Proteomics defines single-cell identity and heterogeneity

Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over the past few decades, immunotherapy has shown remarkable efficacy in the treatment of cancer, particularly the success of immune checkpoint blockade targeting CTLA-4, PD-1 and PDL1, which has led to a breakthrough in tumor immunotherapy. Tumor neoantigens, a new approach to tumor immunotherapy, include antigens produced by tumor viruses integrated into the genome and antigens produced by mutant proteins, which are abundantly expressed only in tumor cells and have strong immunogenicity and tumor heterogeneity. A growing number of studies have highlighted the relationship between neoantigens and T cells’ recognition of cancer cells. Vaccines developed against neoantigens are now being used in clinical trials in various solid tumors. In this review, we summarized the latest advances in the classification of immunotherapy and the process of classification, identification and synthesis of tumor-specific neoantigens, as well as their role in current cancer immunotherapy. Finally, the application prospects and existing problems of neoantigens were discussed.

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Neoantigen: A New Breakthrough in Tumor Immunotherapy.

Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases However, the biological functions of circRNAs in colorectal cancer (CRC) are largely unknown RT-qPCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues Fluorescence in situ hybridization (FISH) was used to analyze the location of circSPARC Function-based experiments were performed using circSPARC knockdown and overexpression cell lines in vitro and in vivo, including CCK8, colony formation, transwell and metastasis models Mechanistically, luciferase reporter assay, western blots, RNA immunoprecipitation (RIP), Chromatin isolation by RNA purification (ChIRP) and immunohistochemical stainings were performed CircSPARC was upregulated in both the tissues and plasma of CRC patients High expression of circSPARC was associated with advanced TNM stage, lymph node metastases, and poor survival Silencing circSPARC inhibited CRC cell migration and proliferation in vitro and vivo Mechanistically, circSPARC sponged miR-485-3p to upregulate JAK2 expression and ultimately contribute to the accumulation of phosphorylated (p)-STAT3 Besides, circSPARC recruited FUS, which facilitated the nuclear translocation of p-STAT3 These findings suggest that circSPARC might serve as a potential diagnostic and prognostic biomarker and a therapeutic target for CRC treatment by regulating JAK2/STAT3 pathway

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The circular RNA circSPARC enhances the migration and proliferation of colorectal cancer by regulating the JAK/STAT pathway

Purpose of review
Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored.

Role of osteocytes in multiple myeloma bone disease

BackgroundMultiple myeloma (MM) is a clonal plasma cell malignancy associated with osteolytic bone disease. Recently, the role of MM-derived exosomes in the osteoclastogenesis has been demonstrated although the underlying mechanism is still unknown. Since exosomes-derived epidermal growth factor receptor ligands (EGFR) are involved in tumor-associated osteolysis, we hypothesize that the EGFR ligand amphiregulin (AREG) can be delivered by MM-derived exosomes and participate in MM-induced osteoclastogenesis.MethodsExosomes were isolated from the conditioned medium of MM1.S cell line and from bone marrow (BM) plasma samples of MM patients. The murine cell line RAW264.7 and primary human CD14+ cells were used as osteoclast (OC) sources.ResultsWe found that AREG was specifically enriched in exosomes from MM samples and that exosomes-derived AREG led to the activation of EGFR in pre-OC, as showed by the increase of mRNA expression of its downstream SNAIL in both RAW264.7 and CD14+ cells. The presence of neutralizing anti-AREG monoclonal antibody (mAb) reverted this effect. Consequently, we showed that the effect of MM-derived exosomes on osteoclast differentiation was inhibited by the pre-treatment of exosomes with anti-AREG mAb. In addition, we demonstrated the ability of MM-derived AREG-enriched exosomes to be internalized into human mesenchymal stromal cells (MSCs) blocking osteoblast (OB) differentiation, increasing MM cell adhesion and the release of the pro-osteoclastogenic cytokine interleukin-8 (IL8). Accordingly, anti-AREG mAb inhibited the release of IL8 by MSCs suggesting that both direct and indirect effects are responsible for AREG-enriched exosomes involvement on MM-induced osteoclastogenesis.ConclusionsIn conclusion, our data indicate that AREG is packed into MM-derived exosomes and implicated in OC differentiation through an indirect mechanism mediated by OBs.

Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis

The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.

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Alternative splicing and cancer: a systematic review.

Circular RNAs (circRNAs) are a very interesting class of conserved single-stranded RNA molecules derived from exonic or intronic sequences by precursor mRNA back-splicing. Unlike canonical linear RNAs, circRNAs form covalently closed, continuous stable loops without a 5'end cap and 3'end poly(A) tail, and therefore are resistant to exonuclease digestion. The majority of circRNAs are highly abundant, and conserved across different species with a tissue or developmental-stage-specific expression. circRNAs have been shown to play important roles as microRNA sponges, regulators of gene splicing and transcription, RNA-binding protein sponges and protein/peptide translators. Emerging evidence reveals that circRNAs function in various human diseases, particularly cancers, and may function as better predictive biomarkers and therapeutic targets for cancer treatment. In consideration of their potential clinical relevance, circRNAs have become a new research hotspot in the field of tumor pathology. In the present study, the current understanding of the biogenesis, characteristics, databases, research methods, biological functions subcellular distribution, epigenetic regulation, extracellular transport and degradation of circRNAs was discussed. In particular, the multiple databases and methods involved in circRNA research were first summarized, and the recent advances in determining the potential roles of circRNAs in tumor growth, migration and invasion, which render circRNAs better predictive biomarkers, were described. Furthermore, future perspectives for the clinical application of circRNAs in the management of patients with cancer were proposed, which could provide new insights into circRNAs in the future.

Review on circular RNAs and new insights into their roles in cancer.

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) plays a key role in regulating mitotic processes, including spindle assembly checkpoint and DNA repair pathways, which may account for Chromosome instability (CIN). As CIN is a predominant hallmark of cancer, TRIP13 may act as a tumor susceptibility locus. Amplification of TRIP13 has been observed in various human cancers and implicated in several aspects of malignant transformation, including cancer cell proliferation, drug resistance and tumor progression. Here, we discussed the functional significance of TRIP13 in cell progression, highlighted the recent findings on the aberrant expression in human cancers and emphasized its significance for the therapeutic potential.

Insights into a Crucial Role of TRIP13 in Human Cancer.

Pain is a widespread and complex symptom which causes serious emotional and social burdens to individuals and society. Most patients with pain rely heavily on over the counter (OTC) and prescription pain killers. However, there would be a number of issues that arise from the use of pain killers, in which safety and addiction are the most critical issues. For traditional Chinese medicine (TCM), pain is a result of the meridians being blocked. This could occur as a symptom of or be caused by various diseases. In this case, the key to relieve pain depends on dredging the meridian or meridians. Acupuncture has been practiced in China for over 2000 years to lessen pain. It is based on the "meridian theory". Acupuncture is being used more widely and with a growing number of people in the treatment of pain because it is safer and has fewer side effects. Along with growing use and interest in acupuncture to treat pain, more attention has been paid to the mechanism underlying its analgesic effect, which is mainly associated with the changes of neurotransmitters. In this review, we summarize and analyze the range and mechanism of acupuncture analgesia treatment.

Research Advances on Acupuncture Analgesia.

Multiple myeloma (MM) is characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM). The interaction between the BM microenvironment and MM plasma cells can influence cell proliferation, drug resistance and prognosis of the disease. The BM microenvironment (BMME) consists of a cellular and non‑cellular compartment. The cellular compartment includes stromal cells, endothelial cells, osteoclasts and osteoblasts, and the non‑cellular compartment includes the extracellular matrix (ECM) and the liquid milieu, which contains cytokines, growth factors and chemokines. The complex interaction between the BM microenvironment and MM plasma cells influences disease development and prognosis. The present review focuses on the interaction between malignant plasma cells and the BM microenvironment during MM progression. An improved understanding of the interaction between MM plasma cells and their microenvironment will enable the development of novel therapeutic tools that can be used in the treatment of MM, a currently incurable blood cancer.

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Jinjun Qian

Papers

Alternative splicing and cancer: a systematic review.

Review on circular RNAs and new insights into their roles in cancer.

Insights into a Crucial Role of TRIP13 in Human Cancer.

Research Advances on Acupuncture Analgesia.

The impact of the bone marrow microenvironment on multiple myeloma (Review)