A brief journey to India, and into models of carcinogenesis

In early 2016, I was asked if I wished to speak at the discussion meeting “Conflict and Competition in Cellular Populations” in Bangalore, India organized by Dr Sandeep Krishna and Dr Sunil Laxman (NCBS). The title sounded so intriguing that I accepted without even checking the actual topic of the meeting. Then an adventure begun, that now concluded (did it?) in 2021 with a small paper entitled “Cooperation of partially transformed clones: an invisible force behind the early stages of carcinogenesis” published in the journal of the Royal Society, Open Science (10.1098/rsos.201532). Let me tell you the story of this journey that, perhaps, might inspire you to adventure outside of your field.

For brevity, I’ll skip the details about the actual trip. It was of course exciting to experience a culture I am often exposed but I never lived. The food, the people, the contrasts of India, a small glimpse into a complex galaxy of humanity. My short trip to India started with a sleep-deprived-me trying to explain to the border police that the conference Conflict and Competition in Cellular Populations, nicknamed CCCP, which poster was written in pseudo-Cyrillic, was not a political conference (I would have needed a different visa in that case!) and concluded back in Cambridge a week later with a slightly embellished bedtime story for my 3 years old daughter about the animals I saw in the park that hosts NCBS, a story that I am still telling now and then to her.

But of course, here I focus on the science. The conference hosted a good number of great speakers (referring to others) on the topic of ecology (er, yes, the title made sense). Suddenly it dawned on me I was ‘a bit’ off-topic. However, I loved talk after talk learning a bit about ecology, including its mathematical foundations. I really enjoyed the meeting, so much so I could not stop thinking about its relevance for my work that back then was focused on non-genetic heterogeneity in cell decisions, carcinogenesis and the DNA damage response.

The study of cancer as an ecological problem is not new, of course. Something very specific started to bug me though, something I could not find literature about. We know that different clones of cancer cells cooperate and compete in tumours but what happens during the very early steps of carcinogenesis? I was queuing to board the airplane when I succeeded to download the paper “Evolution of cooperation among tumor cells” published ten years earlier by Axelrod and colleagues in PNAS. It was a nice in-flight read, but the flight from Bangalore to London is long and I started to obsess about a very simple mathematical fact.

For a moment, let’s imagine you dream of establishing a business but you need £1M to start it. However, you are a bit of an odd person and decide to do it only if you win the lottery which jackpot is £500k. You clearly make strange decisions but I am not here to judge… the oddest thing is, however, that you bet on winning the lottery not just once but twice. Then you have an idea You agree with your village of similarly odd-minded people that if anyone wins the lottery, you will pool the money together to invest in this start-up. This is still an unlikely strategy, and certainly one that has a tiny probability to succeed, but it is definitely more likely to work out than waiting to win the jackpot twice alone.

Back to carcinogenesis. Every day, each cell has a certain probability to mutate because of exposure to radiation, chemicals or simply the chance of errors of biochemical machineries. Mutation after mutation in the right genes, a cell might grow into cancer. A very unlikely series of events that, however, with trillion of cells in our bodies, over one’s lifespan is likely to happen. We know that certain mutations occurs in cells that eventually lead to cancer. We know that one cell wins the macabre lottery of disease multiple times before leading to cancer. We then know that many cells will get mutations within an otherwise healthy tissue.

We usually consider that all these other mutant cells will either accrue neutral mutations (i.e., mutations that will not change the fitness of the cell, nor confer a cancer phenotype), or deleterious mutations that will be purged by tumour suppressive mechanisms. However, cells within a tissue communicate and mutations occurs also in genes responsible of cell-to-cell communication. In my recent work I propose a ‘toy model’ with which I explore the possibility that the gene- and cell- centric mutational process should be reconsidered in the context of an overall tissue where cell-to-cell communication might reshape the early steps of carcinogenesis. I am not the first one doing so, but I try to emphasize with simple modelling how the mutational process should be seen in the context of a collective of cells rather than in a gene- or cell- centric fashion.

What did I learn beyond what I have written in the paper (i.e. in addition to the science)?

First I had really fun, something that over time does not happen with every paper, even those more important ones where we invest major resources in. I even had fun during the revision process. As many of us experience, I often got half of the referees very supportive of my work and half rather dismissive. But those very supportive have been often extraordinary kind and helpful, either defining the manuscript ‘a refreshing read different from what I usually read in this field‘ (earlier submission in a different journal) to ‘the models presented here make the point in a clear and dramatic manner‘. The last referee of the last submission now published was particularly helpful. Not only they critically review the manuscript but also invested time to describe a discrete time Markov chain model that I could have integrated in the manuscript. This suggestion permitted me to learn a bit of maths I did not practise before, and to improve the work… this is what refereeing should be.

Second, alongside the enthusiasm of adventuring in a rather different field from my already eclectic research interests, I also felt the pain of being an outsider; a pain I feel often but that it was made sharper by the fact I was a single author. This was really a ‘pet project’. I got convinced to shape my notes in a manuscript only after I attended a seminar by Prof. Allan Balmain in 2018 related to the Nat Cell Biol article “Multicolour lineage tracing reveals clonal dynamics of squamous carcinoma evolution from initiation to metastasis“. It was a great talk and somehow relevant to the notes I had written since my trip to India. I decided to try to publish my ideas after reading the commentary by Prof. Kornelia Polyak and Prof. Michalina Janiszewska where they state: “One possible explanation is that there is a cooperative interaction between the streak and bulk tumour cell populations; an intriguing hypothesis that warrants further investigation but was not tested by Reeves et al.5. The streak pattern observed by Reeves et al. is reminiscent of the streaks generated by non-mutualistic budding yeast analysed by Muller et al.13.” Eventually, I am not sure the work I had put in this manuscript was worth the pain.

Then, do I advise others to adventure so wildly in other territories? As I have written before, it is rarely rewarding career-wise and never easy. But, once in a while, let’s just follow the passion and enthusiasm for something new, with no regrets. Any adventure comes with some pain but the fun of exploring, eventually, makes the experience worth living overall.

I wish that this small new paper can really provoke some thoughts, or inspire some young scientist to adventure… perhaps not too much and not alone as exploring comes with its perils.

Author: Alessandro

Please visit my website to know more about me and my research http://www.quantitative-microscopy.org

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