Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in ...genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell‐like state. This stem cell‐like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell‐like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell‐intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.
The skin forms a vital barrier between an organism’s external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to ...prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis.
The stringent response to amino acid starvation, whereby stable RNA synthesis is curtailed in favour of transcription of amino acid biosynthetic genes, is controlled by the alarmone ppGpp. To ...elucidate the extent of gene expression effected by ppGpp, we designed an experimental system based on starvation for isoleucine, which could be applied to both wild-type Escherichia coli and the multiauxotrophic relA spoT mutant (ppGpp⁰). We used microarrays to profile the response to amino acid starvation in both strains. The wild-type response included induction of the general stress response, downregulation of genes involved in production of macromolecular structures and comprehensive restructuring of metabolic gene expression, but not induction of amino acid biosynthesis genes en masse. This restructuring of metabolism was confirmed using kinetic Biolog assays. These responses were profoundly altered in the ppGpp⁰ strain. Furthermore, upon isoleucine starvation, the ppGpp⁰ strain exhibited a larger cell size and continued growth, ultimately producing 50% more biomass than the wild-type, despite producing a similar amount of protein. This mutant phenotype correlated with aberrant gene expression in diverse processes, including DNA replication, cell division, and fatty acid and membrane biosynthesis. We present a model that expands and functionally integrates the ppGpp-mediated stringent response to include control of virtually all macromolecular synthesis and intermediary metabolism.
The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein ...that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.
Objectives
To report on our initial experience with intramesenteric (IM) dynamic contrast magnetic resonance lymphangiography (DCMRL) for evaluation of the lymphatics in patients with concern for ...mesenteric lymphatic flow disorders and to compare IM-DCMRL with intrahepatic (IH) and intranodal (IN) DCMRL.
Methods
This is a retrospective review of imaging findings in 15 consecutive patients who presented with protein losing enteropathy (PLE) and/or ascites undergoing IM-DCMRL, IH-DCMRL, and IN-DCMRL. The IM-DCMRL technique involves the injection of a gadolinium contrast agent into the mesenteric lymphatic ducts or lymph nodes followed by imaging of the abdomen and chest with dynamic time-resolved MR lymphangiography.
Results
IM-DCMRL was successfully performed in 14/15 (93%) of the patients. When comparing IN-DCMRL with IM-DCMRL, there was a significant difference in the visualization of dermal backflow (
p
= 0.014), duodenal perfusion (
p
= 0.003), duodenal leak (
p
= 0.014), and peritoneal leak (
p
= 0.003). IM-DCMRL demonstrated peritoneal leak in 7 patients in contrast to IH-DCMRL which demonstrated leak in 4 patients and IN-DCMRL which did not demonstrate any peritoneal leaks. Duodenal leaks were seen by IH-DCMRL in 9 patients versus 5 with IM-DCMRL and none with IN-DCMRL. In one patient with congenital PLE, the three modalities showed different disconnected flow patterns with duodenal leak only seen by IM-DCMRL. There were no short-term complications from the procedures.
Conclusions
IM-DCMRL is a feasible imaging technique for evaluation of the mesenteric lymphatics. In certain mesenteric lymphatic flow abnormalities, such as PLE and ascites, this imaging may be helpful for diagnosis and the planning of interventions and warrants further studies.
Key Points
• Intramesenteric dynamic contrast magnetic resonance lymphangiography (IM-DCMRL) is a new imaging technique to evaluate mesenteric lymphatic flow disorders such as ascites.
• IM-DCMRL is able to image lymphatic leaks in patients with ascites and protein losing enteropathy not seen with intranodal (IN-DCMRL) imaging.
The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are ...associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external “spike” PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.
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•Gag-derived PNMA2 protein is released from cells as non-enveloped virus-like capsids•Recombinant PNMA2 capsids injected into mice induce an autoimmune reaction•Mouse and paraneoplastic patient PNMA2 autoantibodies bind to external capsid epitopes•Mice injected with PNMA2 capsids develop learning and memory deficits
PNMA2 is a domesticated retrotransposon gene associated with cancer-induced paraneoplastic neurological syndromes. Findings here show that PNMA2 protein is exclusively expressed in the brain of mammals and is released as non-enveloped virus-like capsids, which are immunogenic and induce an autoimmune response that leads to neurological deficits when injected into mice.
Background Recent studies suggest that lymphatic congestion plays a role in development of late Fontan complications, such as protein-losing enteropathy. However, the role of the lymphatic ...circulation in early post-Fontan outcomes is not well defined. Methods and Results This was a retrospective, single-center study of patients undergoing first-time Fontan completion from 2012 to 2017. The primary outcome was
≤6 months after surgery, a composite of death, Fontan takedown, extracorporeal membrane oxygenation, chest tube drainage >14 days, cardiac catheterization, readmission, or transplant. Complication causes were assigned to 1 of 4 groups: (1) Fontan circuit obstruction, (2) ventricular dysfunction or atrioventricular valve regurgitation, (3) persistent pleural effusions
Fontan obstruction or ventricular dysfunction, and (4) chylothorax or plastic bronchitis. T2-weighted magnetic resonance imaging sequences were used to assess for lymphatic perfusion abnormality. The cohort consisted of 238 patients. Fifty-eight (24%) developed early complications: 20 of 58 (34.5%) in group 1, 8 of 58 (14%) in group 2, 18 of 58 (31%) in group 3, and 12 of 58 (20%) in group 4. Preoperative T2 imaging was available for 126 (53%) patients. Patients with high-grade lymphatic abnormalities had 6 times greater odds of developing early complications (
=0.001). Conclusions There is substantial morbidity in the early post-Fontan period. Half of those who developed early complications had lymphatic failure or persistent effusions unrelated to structural or functional abnormalities. Preoperative T2 imaging demonstrated that patients with higher-grade lymphatic perfusion abnormalities were significantly more likely to develop early complications. This has implications for risk stratification and optimization of patients before Fontan palliation.
RAS guanosine triphosphatases (GTPases) are mutated in nearly 20% of human tumors, making them an attractive therapeutic target. Following our discovery that nucleotide-free RAS (apo RAS) regulates ...cell signaling, we selectively target this state as an approach to inhibit RAS function. Here, we describe the R15 monobody that exclusively binds the apo state of all three RAS isoforms in vitro, regardless of the mutation status, and captures RAS in the apo state in cells. R15 inhibits the signaling and transforming activity of a subset of RAS mutants with elevated intrinsic nucleotide exchange rates (i.e., fast exchange mutants). Intracellular expression of R15 reduces the tumor-forming capacity of cancer cell lines driven by select RAS mutants and KRAS(G12D)-mutant patient-derived xenografts (PDXs). Thus, our approach establishes an opportunity to selectively inhibit a subset of RAS mutants by targeting the apo state with drug-like molecules.
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•Development of a high-affinity monobody, R15, selective for apo RAS•R15 inhibits RAS mutants with elevated spontaneous nucleotide release rates•>50% of oncogenic RAS mutants may be susceptible to inhibitors binding to apo RAS•Targeting apo RAS represents a viable approach for inhibiting RAS-driven tumors
Khan et al. develop a high-affinity monobody to nucleotide-free RAS that, when expressed intracellularly, inhibits oncogenic RAS-mediated signaling and tumorigenesis. This study reveals the feasibility of targeting the nucleotide-free state to inhibit tumors driven by oncogenic RAS mutants that possess elevated nucleotide exchange activity.
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