The case of a stuttering ink pen- A novel subclass of cancers
Disclaimer: The language of science is concrete, precise, and definitive. Although it is written in English, it is a distinct dialect. But thankfully, science is also about abstractions, theories, and models. With this blog, I aim to convey the abstract core of the story we newly published in Nature Communications.
Before discrete clicks and clacks of the keyboard snatched away our unique cursive pen craft, the fluidity of the navy blue ink gave a clear shape to our thoughts and reflections. Sometimes though, they just remained illegible. Talking about illegible, how can you forget the unreadable penmanship on a doctor’s prescription back in the day? It could only be translated by the local pharmacist to provide appropriate medicines. Quite similarly, inside a human cell, the DNA prescribes the expression of specific genes in the form of an RNA copy in a process termed transcription (like a prescription). This RNA copy is then translated by appropriate enzymes (like a pharmacist) to make proteins for the cell.
This process of transcription and translation is pivotal to the working of any cell, even cancer cells. Of course, the sort of genes in the DNA prescribed, the degree to which they are prescribed, and their mutation status, proffering the cell a distinct growth advantage, distinguish cancer cells from normal cells.
Historically, research in cancer has centered on unearthing novel mutations in cancer-causing genes and discovering therapeutic approaches to annul their destructive effects. One such promising therapeutic approach is immunotherapy (Dr. James P. Allison and Dr. Tasuku Honjothe won the 2018 Nobel Prize in Physiology or Medicine for their work leading to the application of immunotherapy). Unlike chemotherapy (a blanket-strategy targeting fast-growing cancer cells using chemical poisons) or radiotherapy (DNA damaging radiation against fast-growing cancer cells), immunotherapy invokes our immune system to fight cancers more effectively and far more selectively, resulting in dramatic favorable outcomes. However, in a large chunk of cancers, immunotherapy still fails to deliver the goods.
Why is this so? How can we fine-tune it to perform better? The entire cancer research community is still greatly hopeful of the promise immunotherapy holds owing to its much-vaunted potential of halting the seemingly inexorable march of cancer, and is abuzz with likely explanations for the puzzling ability some cancers possess to zig when the immune system decides to zag. Most research groups have focused on the culpable role of numerous non-cancerous cells around a growing tumor. These surrounding cells form a beneficial habitat, termed immuno-suppressive microenvironment in the scientific dialect, and behave like corrupt officials protecting the malignant growth against honest immune cells from attacking it. A case of corrupt politics exists even at the cellular level!
Yet, this fetching view of the antagonist being external to the tumor may only paint half the picture. We in our group grappled long and hard (more than three years and multiple journal rejections, to be precise) with this predicament and looked within for answers, literally within the cancer cell. We peered into the workings of the cancer cell to unspool the knots of the puzzling resistance many cancers display against immunotherapy — from the viewpoint of the stony-eyed scientific dialect, we call it the cell-autonomous mechanism of resistance — and we are happy to report a simple, and yet an unexpected explanation for this puzzle.
To answer this, let us go back to the analogy in the beginning. What if the pen the doctor holds while prescribing the medicine malfunctions? The ink flows at the beginning of the sentence, then stutters in the middle, and then begins to flow again towards the end. You take this prescription to the drug store and then realize the error, it is illegible for you anyway, but even the pharmacist wrestles with it in vain. Finally, you get no medicine.
Likewise, in our Nature Communications study report for the first time, transcription (making an RNA copy of the prescribed gene in the DNA) in a subset of cancers stutter in the middle of specific genes required for a favorable response to immunotherapy. As a result, these cancer cells continue to survive and thrive during immunotherapy. We call such cancers — Transcription Elongation deficient tumors.
This novel classification of Transcription Elongation deficiency in cancers can be clubbed along with a few other biological indicators already used in the clinics, and as a result, we can potentially help segregate patients into responders and non-responders to immunotherapy, thereby averting an unnecessary course of what can be an ill-fated treatment strategy for the identified non-responders.
But what is the Achilles heel of this novel class of tumors? Can we re-sensitize them to immunotherapy? This is the next step. Well, science advances in incremental steps through collective effort. It is this process that excites us. We don’t expect to find the ultimate answers tomorrow but are driven by the search. Right now, we can only hazard a guess, but the reasoning ink in our lab, like any other lab, is streaming through the perceptive pen, sometimes stuttering…skipping…with the occasional abortive pause, but still flowing to formulate a solution to this obstacle as well.
Here is the link to our article.
Defective transcription elongation in a subset of cancers confers immunotherapy resistance: https://www.nature.com/articles/s41467-018-06810-0
Here is a link to the show-and-tell video review on the methodology we used in the paper: https://tinyurl.com/y69v4hke
