Michael McClelland, PhD, Professor

Dr. McClelland's Publications
mmcclelland@skcc.org

Director, Cancer Genetics Program

Laboratory Staff: Steffen Porwollik, PhD, Yipeng Wang, MD, Gaelle Rondeau, PhD, Rocio Canals PhD, Sang Ho Choi MD, Nabil Arrach, Ph.D., Pui Cheng, Huazhen Yao, BS.

Supervisor of Fred Long BS, in Bioinformatics Core.

Supervisor of Xiao Qin Xia. PhD, in Genomics Core.

This laboratory is applying high-throughput methods in a number of areas:

Program 1: Salmonella Genomics.
Background. Salmonellae are among the most important orally acquired pathogens in the world. Approximately one million deaths and 100 million human infections are caused annually by these organisms, and they are major pathogens of domestic livestock. On a genomic level, strains within this species can differ by hundreds of their ~4,500 genes. This variability is the result of a mosaic of lateral transfer events within a constant genome scaffold. These differences result in an extraordinary diversity of host-ranges and pathogenic presentations between strains. Known virulence functions are encoded primarily within these laterally transferred regions. However, despite 30+ years of intensive study, the functions of most genes within these important regions are still unknown. We are in the process of rectifying this gap in knowledge.

Objective. Understand the evolution of pathogenesis in Salmonella with the objective of generating principles applicable to other diseases, allowing new methods of treatment, and also exploitation of avirulent strains for human needs.

Approaches.

A. We have sequenced strains used in laboratory research and are now sequencing 30 more strains that capture the diversity of the species. Understanding sequence diversity:

> Allows steps in evolution to be better understood.
> Allows development of DNA typing methods that correlate better with infectious manifestations.
> Allows the construction of specific in-frame knockouts of every gene (1150 so far) as a critical resource for our functional genomic studies.

B. We have developed oligonucleotides microarrays for high-throughput analysis of:

> RNA expression.
> Screening promoter-GFP libraries for all promoters.
> Studying the fitness of all genomic regions, simultaneously, in animal gut, systemic infection, and the environment.

Program 2: Salmonella as a therapeutic delivery agent in cancer.

Background. Harmless live vaccine strains of Salmonella naturally accumulate 1000X in tumors. Tumors have lower than normal levels of oxygen, where Salmonella will continue to thrive protected from the immune system. Salmonella may also further deplete oxygen to levels thereby killing and growing on the remains of tumor cells. This leads to cures.

Objective. Improve upon the natural ability of Salmonella to kill tumors. In addition, Salmonella can be used to deliver therapeutic agents, such as enzymes for drug metabolism and cytokines.

Approaches. In order to understand and improve the ability of Salmonella to kill tumors, and develop this ability for therapeutic use we are taking the following steps:

> Identifying promoters active in tumors to express therapeutics.
> Identifying mutants that grown better than wild type bacteria in tumors.
> Identifying avirulent strains that grow well in cancer.
> Determining the usefulness of these mutations in a variety of animals so they can be used to treat tumors in companion animals.

Program 3: Biomarkers prostate cancer recurrence after prostatectomy.
Background. Prostate cancer is the most common cancer in men (70% of 70 year olds!). Tens of thousands die each year because the tumor has metastasized before treatment. However, the vast majority of prostate cancers do not lead to death even if untreated but most cases are treated, nevertheless, because there is no test for accurate identification of indolent versus aggressive cases. More than 100,000 men are treated unnecessarily each year in the US, at a cost of billions of dollars, and with some side-effects in most cases.

Objective. Develop prognostic tests to accurately define those patients with progressive disease, so they can be targeted for early aggressive treatment.

Approaches. We accumulated clinical data over decades for hundreds of consented patients.
> Developed method that assigns predictive markers to tumor or adjacent reactive tissues. Note: most biopsies do not contain tumor but changes occur in these samples, nevertheless.
> RNA strategy licensed to company.
> Building large tissue microarrays for protein prognosticators.
> Developing DNA methylation assays (see below).

Program 4: DNA methylation biomarkers for cancer progression.

Background. For prostate cancer, the sources of materials for prognostics include needle biopsies, blood, and urine, as well as prostatectomies. Prognostic tests can include pathology, DNA, RNA, or protein, or combinations thereof. DNA is more stable than RNA and is found in all of these types of samples. The methylation profile is unaltered in partially degraded DNA after cell death.

Objective. Develop a cancer prognosticator based on DNA rather than RNA or protein.

Approaches. We developed method that samples hundreds of thousands of DNA methylation loci throughout genome.

> The prostate tumor samples in Program 3 are being screened to find differences in DNA methylation that are prognostic.
> Markers are being converted to an assay platform that can be used in a clinical service laboratory.

Protocols and Arrays Information

The NCI “Director’s Challenge” program for the Molecular Characterization of Early Stage Prostate Cancer