Daniel W. Vermeer- Sanford Research
Daniel W. Vermeer
- Sanford Research
About
78
Publications
8,849
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
2,071
Citations
Introduction
Current institution
Publications
Publications (78)
The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or...
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1–5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite ou...
Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative le...
Background:
Chemoradiotherapy is a standard treatment for HNSCC. Blockade of the PD-1/L1-2 interaction may represent a target to overcome immune escape during this treatment.
Methods:
Utilizing a HNSCC mEERL C57BL/6 mouse model, we evaluated a PD-1 blockade alone or in combination with cisplatin-based chemoradiotherapy. Next, we evaluated periph...
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a fast-growing health problem in the United States. By analyzing the transcriptomes of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC patient tissues, we previously revealed that expression of CXCL14, constitutively expressed in basal epithelial cells, is down...
Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predomi...
Solid tumors are innervated by nerve fibers that arise from the autonomic and sensory peripheral nervous systems. In prostate cancer, doublecortin-expressing neural progenitors initiate autonomic adrenergic neurogenesis1 which facilitates tumor development and dissemination2, via an angiogenic switch that fuels cancer growth3,4. Similarly, a loss o...
Background
near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that uses antibody-photoabsorber (IRDye700DX, IR700) conjugates (APCs) which bind to target cells and are photoactivated by NIR light inducing rapid necrotic cell death. NIR-PIT targeting human epidermal growth factor receptor (hEGFR) has been shown to destroy hEGFR express...
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecological malignancy, with poor survival rates attributable to both late diagnosis and resistance of tumors to standard-of-care chemotherapies. Recent therapeutic strategies aim to circumvent chemoresistance by targeting tumor-extrinsic factors that support the tumor microenvironment...
Fatigue is a common and debilitating symptom of cancer with few effective interventions. Cancer-related fatigue (CRF) is often associated with increases in inflammatory cytokines, however inflammation may not be requisite for this symptom, suggesting other biological mediators also play a role. Because tumors are highly metabolically active and can...
Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve...
Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, including a subset of head and neck squamous cell carcinoma (HNSCC), resulting in about half a million deaths every year. Persistent infection with high-risk HPV is necessary for development of HPV-associated malignancies. To establish persistence in the host, HPV must evad...
The chemokine CXCL14 is a highly conserved, homeostatic chemokine that is constitutively expressed in skin epithelia. Responsible for immune cell recruitment and maturation, as well as impacting epithelial cell motility, CXCL14 contributes to the establishment of immune surveillance within normal epithelial layers. Furthermore, CXCL14 is critical t...
Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive...
The expression of indoleamine 2,3 dioxygenase (IDO) by tumors can contribute to immunotolerance, and IDO induced by inflammation can also increase risk for the development of behavioral alterations. Thus, this study was initiated to determine whether IDO inhibition, intended to facilitate tumor clearance in response to treatment, attenuates behavio...
The naïve view of tumors as isolated islands of rogue cells has given way to a deeper understanding of cancer as being closer to a foreign organ. This "organ" contains immunologic, vascular, and neural connections to its host that provide not only mechanisms for disease progression but also opportunities for therapeutic intervention. The presence o...
While fatigue is one of the mostly commonly reported side effects of cancer therapy, there is significant variability in intensity and persistence of this symptom. Understanding the factors accounting for this variation may provide insight into mechanisms underlying fatigue. An often overlooked issue is the possible influence of sex differences. Th...
Persistent fatigue affects approximately 20% of cancer survivors. While inflammation and/or alteration in energy metabolism are probably involved in the initiation of fatigue, little is known concerning the mechanisms mediating its persistence. We began to investigate this question by evaluating post-treatment voluntary wheel running in C57BL/6 mic...
Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo model...
The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV[ + ] HNSCC) is rapidly increasing. Although clinical management of primary HPV( + ) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment o...
Patients with densely innervated tumors do worse than those with less innervated cancers. We hypothesize that neural elements are acquired by a tumor-induced process, called neo-neurogenesis. Here, we use PC12 cells in a simple system to test this hypothesis. PC12 cells extend processes, called neurites, only when appropriately stimulated. Using th...
HPV-positive head and neck squamous cell carcinoma (HNSCC) is increasingly frequent. Management is particularly debated in the case of post-surgical high-risk features, i.e., positive surgical margins and extracapsular spread (ECS). In this increasingly complex emerging framework of HNSCC treatment, representative pre-clinical models are needed to...
Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fa...
Purpose
Fatigue is a frequent side effect of cancer and cancer treatment, common to multiple tumor sites and therapeutic strategies. The propagation of peripheral inflammation into the brain is thought to mediate this response. The purpose of this study was to evaluate the role of inflammatory signaling in mediating fatigue induced by multiple syng...
Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease- and treatment-related neurotoxicities appear to be additive, targeting disease-related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related sym...
Human papillomaviruses (HPVs) are causally associated with over 5% of all human cancers including ~25% of head and neck cancers (HNC) and ~100% of cervical cancers (CxCa), resulting in approximately half a million deaths every year. Furthermore, HPV-positive HNC incidence is increasing at an epidemic rate. During decades of cancer progression, HPV...
Patients with cancer often experience fatigue and other symptoms even prior to the start of treatment. Because of the strong association between cancer and inflammation it has been hypothesized that these symptoms are a result of tumor-induced inflammation. We sought to test this hypothesis using a syngeneic heterotopic murine model of human papill...
Unlabelled:
High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we...
Supplemental methods and materials, including ethics statement, reverse transcription-qPCR, bisulfite modification, methylation-specific PCR, bisulfate sequencing, expression vectors, and enzyme-linked immunosorbent assay. Download
Proinflammatory chemokines are upregulated in HPV-positive HNCs and keratinocytes. (A to F) Gene expression levels of chemokines and chemokine receptors were analyzed with HPV-positive (n = 16) and HPV-negative (n = 26) HNCs from our previous global gene expression study (5) as described in the legends to Fig. 1 and Fig. S1 in the supplemental mate...
Chemokine expression profiles of tissue specimens from cervix and head/neck.
Restoration of Cxcl14 expression suppresses tumor growth in vivo. MOE/E6E7 cell clones reexpressing Cxcl14 (clones 8 and 16) and a vector containing MOE/E6E7 cell clone were injected into the rear right flank of wild-type C57BL/6 (A to C) and Rag1−/− (D to F) mice (n = 10 for each group of wild-type mice; n = 7 for each group of Rag1−/− mice). Tumo...
Gating strategy for flow cytometry. The whole spleen from a C57BL/6 mouse was homogenized and stained with a panel of antibodies conjugated to unique fluorophores. Single-stain and no-stain controls were used for fluorescence compensation. A generous large cell gate (forward scatter versus side scatter area), single cell gate (side scatter area ver...
Changes of immune cell populations in TDLNs by Cxcl14 reexpression. MOE/E6E7 cells with Cxcl14 (clones 8 and 16) or the vector were injected into the right flank of C57BL/6 mice (n = 10 for each group). TDLNs were harvested 21 days postinjection. The percentages of antigen-presenting cell (A), neutrophil (B), monocyte (C), and macrophage (D) popula...
CXCL14 downregulation correlates with increased CXCL14 promoter methylation in HPV-positive HNC and CxCa. The TCGA data sets of CXCL14 RNA-seq RSEM (RNA-seq by expectation maximization) counts (mRNA expression) and beta values (DNA methylation) were obtained from cBioPortal (cbioportal.org): HPV-negative HNC, n = 243; HPV-positive HNC, n = 36 (23);...
Changes of immune cell populations in spleens by Cxcl14 reexpression. MOE/E6E7 cells with Cxcl14 (clones 8 and 16) or the vector were injected into the right flank of C57BL/6 mice (n = 10 for each group). Spleens were harvested at 21 days postinjection. The percentages of NK cell (A), CD4+ T cell (B), CD8+ T cell (C), antigen-presenting cell (D), n...
Chemokine expression is deregulated in HPV-associated cancer progression. Chemokines and chemokine receptors with significant changes of expression in CxCa progression are shown in the different panels. (A) IL-8, CXCL9, CXCL11, CCL3, and CCL19; (B) CXCL1, CXCL2, CXCL5, CXCL6, and CCL20; (C) CXCL13 and CCL8; and (D) CXCR2 and CXCR4. The gene express...
Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to precl...
Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60-80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune comp...
The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumo...
As cancer-related symptoms are similar to those of sickness associated with inflammation, it has been proposed that they are also mediated by increased inflammatory cytokines in the brain. However, there is still limited evidence for this relationship. The current study evaluated the alternative possibility that cancer-related symptoms are associat...
Squamous cell carcinomas of the head and neck (SCCHN) are the 6th most common malignancy world-wide with approximately 650,000 diagnoses per year. Human papillomavirus (HPV) causes up to 80% of oropharyngeal (tonsil/base of tongue) SCCHN. Despite presenting at an advanced stage, multiple studies show that HPV+ SCCHN are more curable relative to the...
Standard-of-care cisplatin and radiation therapy (CRT) provides significant tumor control of human papillomavirus (HPV)-mediated head and neck squamous cell carcinomas (HNSCCs); this effectiveness depends on CRT-mediated activation of the patient's own immune system. However, despite good survival, patients suffer significant morbidity necessitatin...
Mitosis is a complex sequence of highly regulated events that ensures the proper segregation of sister chromatids into daughter cells. At the heart of the mitotic machinery lie the microtubules. Microtubules (MTs) are components of the cytoskeleton made up of polymerized alpha and beta tubulin dimers. MT structure and function must be maintained th...
Background
The purpose of this study was to characterize the expression of CD200, a membrane protein that functions in immune evasion, to examine its correlations with cancer stem cell (CSC)-like features and analyze its response to chemotherapy and radiation in human papillomavirus (HPV)-positive (+) and negative (−) head and neck squamous cell ca...
Microtubules (MTs) are components of the cytoskeleton made up of polymerized alpha and beta tubulin dimers. MT structure and function must be maintained throughout the cell cycle to ensure proper execution of mitosis and cellular homeostasis. The protein tyrosine phosphatase, PTPN13, localizes to distinct compartments during mitosis and cytokinesis...
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL
Human papillomaviruses (HPV's) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas. The C-terminus of high risk HPV 16 E6 associates and degrades PTPN13, a non-receptor protein tyrosine phosphatase. PTPN13 has recently been dubbed...
The tryptophan degrading enzyme IDO is expressed by tumor cells and immune cells in the tumor microenvironment. This creates a tolerogenic milieu that compromises tumor clearance. Further, IDO has been shown to be involved in cancer-related fatigue and inflammation-associated depression. As many cancer patients suffer from these symptoms, we sought...
A significant symptom burden is associated with head and neck cancer and the radiation therapy often used in its treatment. These symptoms include fatigue and depression, which have been linked to neuroinflammation. Therefore, this study sought to determine if tumor burden and radiation exposure are sufficient to induce neuroinflammatory processes....
The increasing incidence of human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OSSC) demands development of novel therapies. Despite presenting at a more advanced stage, HPV(+) oropharyngeal squamous cell carcinoma (OSCC) have a better prognosis than their HPV(−) counterparts. We have previously demonstrated that clearance of...
Most head and neck squamous cell carcinomas (HNSCC) over-express ERBB1/EGFR, but EGFR- targeted therapies have yielded disappointing clinical results in the treatment of this cancer. Here we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the pres...
Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response...
Tumor growth with no chemoradiation
Naïve C57BL/6 (n=6) were injected with 1×106 mEERL cells and followed for growth. One week after implantation tumors enter into log phase growth with none of the mice surviving without treatment, and all mice needed to be euthanized after 30 days. This illustrates the necessity for chemoradiation in order for the...
In non-cancerous cells, phosphorylated proteins exist transiently, becoming de-phosphorylated by specific phosphatases that terminate propagation of signaling pathways. In cancers, compromised phosphatase activity and/or expression occur and contribute to tumor phenotype. The non-receptor phosphatase, PTPN13, has recently been dubbed a putative tum...
Tyrosine kinases, like the ErbB and Src families, can mediate potent oncogenic growth and are successful therapeutic targets of human cancers. However, many cancer cells overcome or successfully modulate these downstream signaling cascades in the absence of growth factor or kinase over-expression. We have previously identified a cellular phosphatas...
The ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common cause of cystic fibrosis. The mutation disrupts biosynthetic processing, reduces channel opening rate, and decreases protein lifetime. In contrast to human CFTR (hCFTR)-ΔF508, mouse CFTR-ΔF508 is partially processed to the cell surface, alth...
Bovine adeno-associated virus (BAAV) can enter a cell either through a transcytosis or transduction pathway. We previously demonstrated that particles entering via the transcytosis pathway can be redirected to transduce the cell by blocking particle exocytosis with tannic acid (TA). To investigate whether this approach is useful in lung gene therap...
Gene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV...
Progress toward understanding the pathogenesis of cystic fibrosis (CF) and developing effective therapies has been hampered by lack of a relevant animal model. CF mice fail to develop the lung and pancreatic disease that cause most of the morbidity and mortality in patients with CF. Pigs may be better animals than mice in which to model human genet...
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. The most common mutation, a deletion of the phenylalanine at position 508 (ΔF508), disrupts processing of the protein. Nearly all human CFTR-ΔF508 is retained in the endoplasmic reticulum and degraded, preventing maturation to the plasma membrane. In...
Variola virus, the causative agent of smallpox, enters and exits the host via the respiratory route. To better understand
the pathogenesis of poxvirus infection and its interaction with respiratory epithelia, we used vaccinia virus and examined
its interaction with primary cultures of well-differentiated human airway epithelia. We found that vaccin...
Compounds that enhance either the function or biosynthetic processing of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel may be of value in developing new treatments for cystic fibrosis (CF). Previous studies suggested that the herbal extract curcumin might affect the processing of a common CF mutant, CFTR-DeltaF508. He...
To better understand the function of the conserved C terminus of the cystic fibrosis (CF) transmembrane conductance regulator, we studied constructs containing deletions in the C-terminal tail. When expressed in well differentiated CF airway epithelia, each construct localized predominantly to the apical membrane and generated transepithelial Cl(-)...
In developing gene therapy for cystic fibrosis (CF) airways disease, a transgene encoding a partially deleted CF transmembrane conductance regulator (CFTR) Cl- channel could be of value for vectors such as adeno-associated virus that have a limited packaging capacity. Earlier studies in heterologous cells indicated that the CFTR R (regulatory) doma...
Phosphorylation of the regulatory (R) domain initiates cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel activity. To discover how the function of this domain is determined by its structure, we produced an R domain protein (R8) that spanned residues 708-831 of CFTR. Phosphorylated, but not unphosphorylated, R8 stimulated acti...
