Reciprocal epigenetic Sox2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

Growth factors in the tumor environment are key regulators of cell survival and anoikis resistance during metastasis. Here we reveal significant dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream SMAD effectors in regulation of anchorage-independent tumor cell survival in ovarian cancer. Gene expression profiling uncovered the transcription factor Sox2 as a key signaling node regulated in an opposing manner by anoikis-promoting BMP2 4 and 9 and anoikis-suppressing TGF-β and activin A. Mechanistically, repression of Sox2 by BMPs is mediated by type I receptors ALK2 and ALK3 induced SMAD1 activation, leading to SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2s promoter. Conversely, TGF-β and activin A promote Sox2 expression directly by ALK5-mediated SMAD3 activation and histone H3K4me3 recruitment. Increased Sox2 expression promotes anoikis resistance, while decreasing Sox2 levels conversely reduces anoikis resistance and activates cell death pathways. Additionally, administrating BMP9 as a strategy to reduce Sox2 robustly inhibits intraperitoneal tumor burden and increases survival in multiple ovarian cancer xenograft models. Importantly, BMP-driven SMAD1 signaling can override the effects of TGF-β and activin on Sox2 regulation, which has potential clinical significance as we find high TGF-β levels in patient ascites. Our findings highlight the contrasting regulation of anoikis by distinct SMAD signaling pathways that are dependent on a novel dichotomous regulation of Sox2 and implicate the use of a subset of BMPs as a therapeutic strategy in cancer

The dark and light sides of extra-tumor environment

The paradox in the pathobiological processes driving the incidence and progression across carcinomas unveil new opportunities for effective cancer treatment. The scattered evidence across the literature indicates that the insufficiencies/alterations in mesothelial cell migration, development, or function dramatically change the clinical disease course. We succinctly report in-general phenomena extensible across carcinomas predisposing to desmoplasia/reactive stroma, with due understanding of the limitations associated with such broader extrapolation. We further highlight the need for a comprehensive understanding of these purported pathways with an emphasis towards determining the tradeoffs between the risks associated with cancer susceptibility and disease progression.

The Role of miRNA in Regulating the Fate of Monocytes in Health and Cancer

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic target. At the site of a tumor, monocytes/macrophages constitute a major population of infiltrating leukocytes and, depending on the type of tumor, may play a dual role as either a bad or good indicator for cancer recovery. The functional activity of monocytes and macrophages derived from them is tightly regulated at the transcriptional and post-transcriptional level. This review summarizes the current understanding of the role of small regulatory miRNA in monocyte formation, maturation and function in health and cancer development. Additionally, signatures of miRNA-based monocyte subsets and the influence of exogenous miRNA generated in the tumor environment on the function of monocytes are discussed.

CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.

Identification and Validation of CYBB, CD86, and C3AR1 as the Key Genes Related to Macrophage Infiltration of Gastric Cancer

Gastric cancer (GC) is rampant around the world. Most of the GC cases are detected in advanced stages with poor prognosis. The identification of marker genes for early diagnosis is of great significance. Studying the tumor environment is helpful to acknowledge the process of tumorigenesis, development, and metastasis. Twenty-two kinds of immune cells were calculated by CIBERSORT from Gene Expression Omnibus (GEO) database. Subsequently, higher infiltration of macrophages M0 was discovered in GC compared with normal tissues. WGCNA was utilized to construct the network and then identify key modules and genes related to macrophages in TCGA. Finally, 18 hub genes were verified. In the PPI bar chart, the top 3 genes were chosen as hub genes involved in most pathways. On the TIMER and THPA websites, it is verified that the expression levels of CYBB, CD86, and C3AR1 genes in tumor tissues were higher than those in normal tissues. These genes may work as biomarkers or targets for accurate diagnosis and treatment of GC in the future. Our findings may be a new strategy for the treatment of GC.

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasms (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

Simulating tumor growth using mathematical and agent-based modeling

In this paper, two different approaches for tumor growth modeling are presented and implemented. In the first part of the paper, a macroscopic approach using a PDE model, where the tumor is viewed as a cell mass, is implemented using the level-set method to track the tumor moving boundary in one hand by using Darcy’s law to compute the normal velocity of the free boundary and on the other hand using the shape optimization to draw the normal velocity. In the second part of the paper, a microscopic approach, which focuses on the cellular scale, is presented. A hybrid model using agent-based modeling for the cell behavior and a PDE for the description of the tumor environment is presented. A sensitivity analysis is performed on the hybrid model for a better understanding of its impact on the tumor growth. Numerical experiments are provided for the proposed approaches.

Effect of Toxoplasma gondii on colon cancer growth in mouse model

Despite all advances in cancer treatment methods, failure of treatment is a major concern. This failure can be caused by tumor environment made by tumor cells and prevents immune system to reach neoplastic cells. So, cancer immunotherapy and target therapy are in the focus of scientists. Due to the inverse relationship shown between parasites and cancer, parasites are a candidate for use in cancer immunotherapy. Toxoplasma gondii is an intracellular parasite invades many cells of vertebrae spices but make symptoms only in fetus and immuno-deficient person. Studies have shown T. gondii can stimulate immune system against neoplastic cells and break fort of tumor environment. In this experimental work, Colon cancer bearing mice randomly divided into three groups. Groups 1 and 2 were injected with either lysate or irradiated tachyzoite of T. gondii respectively. The third group were left intact as control group. Our resulted data showed that in irradiated tachyzoite or lysate treated groups there was a significant reduction in tumor growth in comparison with control group. However, the difference in survival time was not statistically significant. In conclusion, treatment with T. gondii antigens resulted in suppression of tumor growth.

Effect of Toxoplasma gondii on colon cancer growth in mouse model

Despite all advances in cancer treatment methods, failure of treatment is a major concern. This failure can be caused by tumor environment made by tumor cells and prevents immune system to reach neoplastic cells. So, cancer immunotherapy and target therapy are in the focus of scientists. Due to the inverse relationship shown between parasites and cancer, parasites are a candidate for use in cancer immunotherapy. Toxoplasma gondii is an intracellular parasite invades many cells of vertebrae spices but make symptoms only in fetus and immuno-deficient person. Studies have shown T. gondii can stimulate immune system against neoplastic cells and break fort of tumor environment. In this experimental work, Colon cancer bearing mice randomly divided into three groups. Groups 1 and 2 were injected with either lysate or irradiated tachyzoite of T. gondii respectively. The third group were left intact as control group. Our resulted data showed that in irradiated tachyzoite or lysate treated groups there was a significant reduction in tumor growth in comparison with control group. However, the difference in survival time was not statistically significant. In conclusion, treatment with T. gondii antigens resulted in suppression of tumor growth. Keywords: Toxoplasma gondii; Cancer; Immunotherapy; Tumor; Mouse model

Reliable evaluation method of heating power of magnetic nanofluids to directly predict the tumor temperature during hyperthermia

Reliable measurement of heating power of magnetic nanofluids (MNs) to accurately predict the AC heat-induction performance in tumors is highly desirable for clinical magnetic nanofluids hyperthermia (MNFH) application because it can save time for screening the performance of newly developed MNFH agent and minimize the over-use of animals dramatically. Here, a bio-mimicking phantom model, called Pseudo-Tumor Environment System (P-TES), biochemically designed by considering the external and internal critical factors related to the complex biological environments is proposed to provide a highly reliable evaluation method of heating performance of MNs for in-vivo MNFH applications. According to the experimentally analyzed results, the heating power of MNs measured using the P-TES is well accorded with the heating temperature measured in the tumors during in-vivo MNFH. This result strongly demonstrates that the proposed P-TES can be recommended as a standardized measurement method of heating performance of MNs for clinical MNFH application.