At least two "valleys of death" have been identified in the spectrum of biomedical research where blockage occurs in translating advances in scientific knowledge to clinical practice and decision making1. One "valley" is the translation of basic scientific knowledge to create new diagnostic techniques or therapeutic interventions that can be used in the care of patients. The analysis of human biospecimens can help cross these barriers. The analysis of biospecimens are used to either confirm the biochemical/biophysical/genetic mechanisms of disease or to test biospecimens in the workup of new diagnostic procedures or confirmation of biological outcomes of therapeutic interventions. It is the difficulty and expense in obtaining appropriate groups of human biospecimens to do such studies that contribute greatly to the obstacles in advancing biomedical research.
The break-through technology of tissue microarrays (TMAs) invented by Kallioniemi and colleagues in the 1990s2 addresses the issues of obtaining sufficient human tissue biospecimens and using them efficiently and cheaply in experimental assays. In this technique up to several hundred different small samples of human tissue are placed in a gridded array in a block of paraffin wax only a few square centimeters in size. Once assembled each paraffin block can be sectioned into about 100 histologic sections and placed on glass slides for the analysis of protein or RNA content of specific gene products. The important thing to remember here is that instead of an assay being performed separately on a hundred different specimens, the assay can be done one time on a single glass slide and provide data on an entire population of patients3. One TMA can ultimately provide tens of thousands of data points and can save thousands to tens of thousands of dollars in assay expense. The CHTN has utilized this technology to create several TMAs to survey populations of specific cancer types, normal organ tissues or the steps of neoplastic progression of specific cancer types4.
A recent publication highlights the utility of TMAs so quickly to confirm a hypothesis in a cohort of human tissue biospecimens. Andricovich et al studies the role of the KDM6A gene in human pancreatic cancer5. Previous genomic analyses suggested a role of this gene in pancreatic tumorigenesis. This group provided functional proof of this in a transgenic mouse model where pancreas-specific KDM6A loss caused pancreatic cancer. To understand if this experimental finding had a correlate to human disease, tissue microarrays, including the CHTN pancreatic tumor progression TMA, were used in assays of KDM6A protein expression. The results indicated that KDM6A was indeed commonly lost in pancreatic cancer compared to normal pancreatic tissue and more poorly-differentiated cancers and metastatic cancers were most likely to have lost expression of this gene. Moreover, this research team identified a potential therapy which targets this pathway, creating a path for testing a new therapy in pancreatic carcinoma based on a specific molecular attribute that can be analyzed in patient tumors. The CHTN is pleased it had a role to play in supporting yet another ground-breaking study in a major human disease.
1. Meslin EM, Blasimme A, Cambon-Thomsen A. Mapping the translational science policy 'valley of death'. Clinical and Translational Medicine. 2013:2:14-.
2. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schrami P, Leighton S, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Med. 1998; 4:844-7.
3. Hernandez BY, Frierson HF, Moskaluk CA, Li YJ, Clegg L. Cote TR, et al. CK20 and CK7 protein expression in colorectal cancer: demonstration of the utility of a population-based tissue microarray. Hum Pathol. 2005;36(3):275-81.
4. Currently available tissue microarrays from the CHTN 2018 [Available from: https://chtn.sites.virginia.edu/tissue-microarrays.
5. Andricovich J., Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. Cancer Cell. 33(3):512-26.e8.