Immunomodulatory roles of PARPs: Shaping the tumor microenvironment, one ADP-ribose at a time.

PARPs encompass a small yet pervasive group of 17 enzymes that catalyze a post-translational modification known as ADP-ribosylation. PARP1, the founding member, has received considerable focus; however, in recent years, the spotlight has shifted to other members within the PARP family. In this opinion piece, we first discuss surprising findings that some FDA-approved PARP1 inhibitors activate innate immune signaling in cancer cells that harbor mutations in the DNA repair pathway.

Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction.

Activation of nucleic acid sensors in endothelial cells (ECs) has been shown to drive inflammation across pathologies including cancer, atherosclerosis and obesity. We previously showed that enhancing cytosolic DNA sensing by inhibiting three prime exonuclease 1 (TREX1) in ECs led to EC dysfunction and impaired angiogenesis. Here we show that activation of a cytosolic RNA sensor, Retinoic acid Induced Gene 1 (RIG-I) diminishes EC survival, angiogenesis and triggers tissue specific gene expression programs.

Consequences of fear effect and prey refuge on the Turing patterns in a delayed predator-prey system.

This study presents a qualitative analysis of a modified Leslie-Gower prey-predator model with fear effect and prey refuge in the presence of diffusion and time delay. For the non-delayed temporal system, we examined the dissipativeness and persistence of the solutions. The existence of equilibria and stability analysis is performed to comprehend the complex behavior of the proposed model.

Dietary and lifestyle associations with microbiome diversity.

Background: Microbial dysbiosis has been closely linked with colorectal cancer development. However, data is limited regarding the relationship of the mucosal microbiome, adenomatous polyps and dietary habits. Understanding these associations may elucidate pathways for risk stratification according to diet.

A Cell-Based Screen Identifies HDAC Inhibitors as Activators of RIG-I Signaling.

Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors, activation of the RNA sensor Retinoic Acid-inducible Gene (RIG-I) using small hairpin RNAs has been shown to elicit powerful innate and adaptive immune responses. Given the challenges inherent in pharmacokinetics and delivery of RNA based agonists, we set out to discover small molecule agonists of RIG-I using a cell-based assay.

Colonic Microbial Abundances Predict Adenoma Formers.

Objective: We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation.

Summary Background Data: Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions.

Methods: Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers.

Nucleic Acid Sensing in the Tumor Vasculature.

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain an immunosuppressive microenvironment.

MicroRNA-494 Regulates Endoplasmic Reticulum Stress in Endothelial Cells.

Defects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress.

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature.

A Distinct Innate Immune Signature of Early Onset Colorectal Cancer.

Despite a decrease in the prevalence of colorectal cancer (CRC) over the last 40 y, the prevalence of CRC in people under 50 y old is increasing around the globe. Early onset (≤50 y old) and late onset (≥65 y old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression.

Differential Expression of PEG10 Contributes to Aggressive Disease in Early Versus Late-Onset Colorectal Cancer.

Background: Colorectal cancer is a leading cause of cancer-related death. Early onset colorectal cancer (age ≤45 y) is increasing and associated with advanced disease. Although distinct molecular subtypes of colorectal cancer have been characterized, it is unclear whether age-related molecular differences exist.

Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase.

Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs).

Integrin CD11b activation drives anti-tumor innate immunity.

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth.

MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling.

MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex.

microRNA-451a regulates colorectal cancer proliferation in response to radiation.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis.

MicroRNAs in Cancer: challenges and opportunities in early detection, disease monitoring, and therapeutic agents.

Purpose Of Review: The goals of this review are to examine the usefulness of miRNAs as diagnostic and prognostic biomarkers for cancer and to evaluate the applicability of miRNAs as cancer therapeutics.

Recent Findings: Examination of miRNA milieu from body fluids offers a new alternative for quick, affordable and easy analysis of disease status in patients. Blood-based exosomal miRNAs have increased stability and are an excellent choice for clinical cancer diagnostics and prognostics.

Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

Objective: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies.

Summary Background Data: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers.

Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions.

In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver.

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment.

Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo.

Kinase-independent role for CRAF-driving tumour radioresistance via CHK2.

Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response.

An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib.

Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting.

Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration.

A brief primer on microRNAs and their roles in angiogenesis.

Development of the vasculature is a complex, dynamic process orchestrated by a balance of pro and anti-angiogenic signaling pathways. The same signaling pathways are mis-regulated and exploited during pathological angiogenesis in cancer, inflammation and cardiovascular diseases and contribute to disease progression. In the last decade, small non-coding RNA molecules termed microRNAs (miRs) have emerged as key regulators of several cellular processes including angiogenesis.