Yet Another Study Agrees: Functional Profiling Provides Insight
January 18, 2013 1 Comment
It was during the last weeks of December that a particularly interesting article crossed my desk. The study done by a group from Toronto, Canada, is entitled Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer. The study examined the proliferative capacity and drug sensitivity in colorectal cancer cells that were tracked using a process known as lentiviral lineage tracking. The investigators showed that despite serial passages, the cell populations remained stable from a genomic standpoint.
What was most interesting was the finding that these genomically related subpopulations became progressively more resistant to oxaliplatin after drug exposure, suggesting what they described as “inherent functional variability.”
As one of several investigators engaged in the field of functional profiling (EVA-PCD), I found the article both interesting and extremely consistent with our laboratory observations. First, cancer cells display biological differences that may reflect environmental (microenvironmental) influences, epigenetics and other drivers not readily identified at the DNA level.
Second, these investigators, using extremely sophisticated molecular techniques, found, as the lead investigator said, “We should not be putting our eggs exclusively in the genetics basket.” This quote from the lead investigator, John Dick, was particularly resonant.
As many of you who read my blogs know, a recurring theme in these pages is the need to broaden our scope and examine the protein, metabolic and functional characteristics of the cancer cells in their native state. Once again we find that as our most accomplished molecular brethren drill down to the bedrock of cancer biology, they are confronted by complexities and crosstalk that can only be effectively studied at the level of cell biology.
I wish all of readers of this blog a happy New Year, and look forward to a healthy and productive 2013.
About Dr. Robert A. Nagourney
A New England Journal of Medicine (366:883-892, March 8, 2012) article described how intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized medicine and biomarker development. This intratumor heterogeneity issue is not a new revelation to cell function analysis.
According to a study published in Molecular Cancer Therapeutics, there is a need to analyze tumor specimens at the time of ovarian cancer recurrence, because they found significant changes in molecular characteristics for some biomarkers. This type of profiling does not take into account changes that can occur in recurrent ovarian tumors. This had been published in 1983, 1984, 1986 by cell function analysis.
A study published in the journal Cell Stem Cell uncovered a case of mistaken identity that may have a significant impact on future breast cancer treatment strategies. They were able to distinguish four kinds of breast cancer that were distinct on the basis of their genetic makeup. These were rough categories and there were divisions within them.
What’s more important than what genes are in the DNA is what genes are actively making RNA, which RNA is actively making protein, which protein is being turned off or turned on, and how all of the proteins in the cell are interacting with each other.
The only way to get the latter information, which is ultimately what you want, is to treat the patient with phenotype analysis. In drug selection, phenotype analysis doesn’t dismiss DNA testing, it uses all the information, measuring the interaction of the entire genome, to design the best treatment for each individual.
I like the analogy of Dr. Scott L. Shreeve about functionality. Anyone familiar with cellular biology knows that having the genetic sequence of a known gene (genotype) does not equate to having the disease state (phenotype) represented by that gene. It requires specific cellular triggers and specialized cellular mechanisms to literally translate the code into the work horse of the cellular world – proteins.
As a result, while genomics provides a methodology to understand the sheet music of life, there is more interest in the proteomic symphony that results by literally bringing the dead notes to life. Since the actual performance of the sheet music can vary, based on the whims of the composer, there is the individual variation or free-lancing of the orchestral performers.
So while the sheet music is absolutely essential to even contemplate a symphonic performance, no one goes to listen to the sheet music. It is the individual performances, the living-breathing-audible-panoramic-splended-view of the whole chamber coming to life that ultimately stirs the soul.
In an analogous fashion, the proteins are the cellular accessories that literally add life to an otherwise staid genetic makeup. Infinitely more variable, infinitely more possibilities, and as a result, infinitely more interesting.