Health

Chaos and cancer — a labyrinth of impossible complexity

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This blog describes our work, wherein we have modeled a certain kind of chaos fermenting within the cancer cell. However, before I explain the implications of this chaos, it is sensible to peer into the landscape of order and diversity.

A question some of us have invariably considered in various situations of life is, what accounts for the appearance and persistence of durably diverse human cultures around the world?

Human cultural diversity can primarily be interpreted as variation in population behavior which is faithfully transmitted to each successive generation within a cultural group. There is no surprise that we value traditions, but we also value liberty. Therefore, not every member of a cultural community is behaviorally identical. In practice, diverse human cultures are made up of individuals, each of whom has a distinct blend of behaviors. In the same way, genomes (the complete set of all genes) in the human body are transmitted faithfully (like tradition) from dividing cells to their offspring. The minor changes that occur during such transmission provide a natural source of genetic variation.

However, in cancers, this natural genetic variation is intensified progressively. Early malignant clonal populations may acquire mutations leading to diverse subpopulations with varying degrees of abnormal genetic variation, dubbed as genomic instability. These cancerous subpopulations are in competition with each other because genomic instability allows for accelerated access to different and potentially advantageous changes for the tumor.

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Nevertheless, cancers aren’t entirely like the Joker; his motive lacked any real purpose other than to see the disorder and mayhem continue. Cancers don’t opt for chaos just for the sake of it. They co-opt a certain level of genomic instability if the risk to cost ratio is low. Unlike the Joker, cancers seem to appreciate which side of the bread is buttered.

The suspicion harbored by anti-tumor immune cells towards a cancerous growth becomes fatal certainties if too many genetic alterations are sensed from within a cancer cell. This is reminiscent of a scene where cops are encircling a bank being robbed. Since the potential for chaos and confusion is high, cops always respond quickly to a bank robbery in progress. Similarly, heightened genomic instability hurls red flags of various sort for the immune cells to pick up and respond. In fact, the presence of anti-tumor immune cells around a tumor (categorized as immunologically ‘hot’ tumors) is a strong correlate of a favorable clinical response to immunotherapy.

Consequently, the traditional model of cancer genome instability is: high genomic instability = immunologically ‘hot’ tumors = favorable response to immunotherapy.

In our work, we provide evidence against this traditional model. Yes, we inject a little bit of upheaval to the conventional view ourselves. In essence, building on the paradoxical observation by Davoli T et al. in 2017, we show that tumors with chromosomal instability (a certain kind of genomic instability), behave very differently.

Chromosomally unstable tumors, although characterized by significant internal aberrations in the chromosome (packaged DNA), appear to preclude the entry of anti-tumor immune cells by switching-off all red flags. They turn immunologically ‘cold’ not ‘hot.’ In other words, they are like banks being robbed which don’t send any red flags or alarm signals, and the cops have no communication to encircle the bank. There is anarchy within the cancer cell but nothing visible on the outside.

In collaboration with Dr. Guido Kroemer’s group in France, we modeled the growth of chromosomally unstable tumors in mice, in the presence and absence of anti-tumor immune surveillance.

To our surprise, we observed that chromosomally unstable tumors, when held to the fire of the anti-tumor immune cells, learned to evade them in a single generation of mice bearing these tumors. A process we imagined to be glacially slow actually happens in a reasonably quick time-frame. Our analyses suggest that they suppress APP genes (genes for warning signs and red flags) by epigenetic silencing. Meaning, this epi- (Greek for ‘above’) genetic process overrides ‘the red flag’ message of the DNA sequences in the cancer cells without actually mutating them.

An interesting exception that defines our rule is provided by chromosomally unstable human brain tumors, namely, GBM (Glioblastoma multiforme) and LGG (Low-Grade Glioma) growing in the immune-privileged status of the brain. Since the brain mostly lacks active immune-surveillance, we don’t observe the same epigenetic adaptation seen in chromosomally unstable tumors growing outside the brain, under strong immune-surveillance.

Finally, we also recommend potential intervention strategies to reactivate the anti-tumor immune cells in chromosomally unstable (CIN+) tumors.

Link to our research article: https://www.tandfonline.com/doi/full/10.1080/2162402X.2019.1657374?nav=Funding

Schematic model of the evolution of CIN+ tumors.

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