The Vortmeyer Laboratory was set up at Yale in October 2008. The research focus in this laboratory continues Dr. Vortmeyer’s past decade’s work at the National Institute of Neurological Disorders and Stroke (NINDS).

Tumor suppressor gene syndromes

Hereditary Tumor Suppressor Gene (TSG) syndromes include von Hippel-Lindau (VHL) disease, Multiple Endocrine Neoplasia type 1, tuberous sclerosis, nevoid basal cell carcinoma syndrome, BRCA1-related breast cancers, among many others . Patients with TSG syndromes inherit a mutated and dysfunctional copy of the referred gene (“first hit”). According to Knudson’s seminal “Two Hits” hypothesis, inactivation of the second wild-type copy of the TSG is required to initiate tumorigenesis (“second hit”). While Knudson’s hypothesis elegantly explains the “initiation” of carcinogenesis, it does not explain the occurrence of specific tumor types in selected organs only, which is characteristic for each TSG syndrome. Furthermore, increasing evidence indicates that TSG deficiency is necessary, but not sufficient for carcinogenesis. Additional genetic and epigenetic changes (“third hit”) must occur after the “second hit” to transform affected cells into cancer. Via molecular and histological analyses, Vortmeyer’s recent works on VHL disease (see Figure 1) and BRCA1-related breast cancer (see Figure 2) have demonstrated that TSGs play important roles in cell determination and differentiation.

These works have begun to shed some lights on the questions of tumor specificity and tumor selectivity by linking TSG function to tissue development. In particular, increasing evidence is being reported that these TSGs play important roles in stem cell determination, from the early asymmetric division of stem cells to maintaining characteristics of fully differentiated cells. Furthermore, inactivation of TSGs during critical periods of embryogenesis leads to accumulations of incompletely differentiated cells in adult tissues, the detection and characterization of which continues to be a major focus of this laboratory.

Figure 1

Figure 1. VHL disease

Figure 2

Figure 2. BRCA1-related breast cancer

Molecular Biology-/Proteomics-based Research on Clinical Specimens

The emphasis of this laboratory is the thorough analysis of diseased human tissues to either validate results obtained in experimental models or to create new original hypotheses. Our approaches include up-to-date proteomic approaches and other molecular profiling tools to distinguish pathologies from normal tissues (therapeutic targets screening), to distinguish pathologies from other pathologies (diagnostic markers screening), and to distinguish the molecular changes within a specimen procured at different conditions (molecular quality evaluation for research specimens). Our approaches also include thorough morphologic-structural analysis with 3D reconstruction. Running projects include:

Figure 3

Development of Alzheimer’s therapeutic targets from autopsy specimens

Figure 4

Identification of diagnostic markers for primary brain tumors.

Figure 5

Exploration of indicators for molecular-quality evaluation in research specimens.

Biospecimen Core for Grant-Supported Biospecimen Preparation

Analysis of diseased human tissues is crucial to obtain new relevant insight into the pathogenesis of disease. The National Cancer Institute’s recent guide to best practices for biospecimen resources describes how recent advances in biomolecular technology have created a need for improved standard operating procedures for human specimen based research and clinical care. Specimens must be biochemically intact and representative of the disease process being evaluated. By addressing a number of key issues, we have optimized tissue procurement and preservation for research on biospecimens—this effort has allowed us to participate in several applications for biospecimens-related research grants. Our particular expertise are challenges related to the following:

Figure 6

Figure 6.

Structural heterogeneity of diseased tissues (see Figure 6) shows a fragment of brain resected from a glioma patient).

Figure 7

Figure 7

Structural heterogeneity of disease processes, and biological heterogeneity of neoplastic disease (see Figure 7) shows a malignant glioma composed of glioma tissues of different histologic grades).

Figure 8

Figure 8.

Biological heterogeneity of tumors (avoidance of nonviable necrotic areas, appreciation of tumor constituents including neoplastic, reactive pre-existent and reactive inflammatory cells (see Figure 8).

We have applied several ancillary technologies to identify, sample, and morphologically control microscopic tissue structures to make them accessible for molecular studies, frequently under application of selective microdissection techniques.