Decoding Cancer Cell and Immune Cell Crosstalk: Investigating Cancer in the Metastatic Niche

The principal research question for this project is how cancer cells and immune cells cooperate to promote the metastatic progression and to colonise a distant site. The first aim of this project is to understand which subpopulations of immune cells are involved in the formation of metastatic niches and the metastatic progression. Specifically, how does the presence of a particular type of immune cell affect the rate of metastatic spread? We aim to study this by comparing clinical samples from patients with an aggressive metastatic spread to samples from patients with an indolent rate of metastasis, as well as studying tissue from immunodeficient mice implanted with patient-derived, spontaneously metastasising neuroblastoma xenografts.
The second aim is to uncover how primary and disseminated tumour cells shape the immune microenvironment at different metastatic niches. In practice, in a mouse model of metastatic disease, how does blocking a particular cytokine secreted by cancer cells alter the composition of the immune landscape, compared to a wild-type model? We will use single-cell RNA-sequencing to analyse expression profiles of tumour and immune cells from primary and metastatic tumours. Our aim is to identify tumour cell populations that extensively signal to stromal or immune cells, enabling us to describe which cytokines that could be targeted for intervention. We will also use spatial transcriptomics to analyse the gene expression in metastasised tumour cells from clinical samples, which we will correlate to the observed proportions of immune cell populations in turn measured using multiplex immunofluorescence.
Lastly, our third aim is to enhance our understanding of cancer's metastatic organotropism (the tendency to preferentially metastasize to specific organs) and the potential influence of immune cells on this process. In other words, how does the immune landscape and the gene expression profiles of metastatic tumour cells compare between organs? We hope to answer this question by running differential gene expression analysis on single-cell transcriptomics data from both primary tumour cells and metastatic tumour cells in xenografted mice and by describing the immune landscape at different metastatic sites. Since the final question is purely descriptive in nature, it does not lend itself well to a ‘PICO’ format.
We hypothesise that the formation of metastatic niches is supported by immune cells with a particular phenotype. We also hypothesise that certain transcriptomic signatures in the tumour cells predispose them to metastasising to a specific organ. Finally, we believe that tumour cells themselves may be involved in priming the tumour microenvironment, including the immune landscape, at the future metastatic site.

In 2020, a population roughly the size of Portugal died of cancer worldwide. Most of these deaths are caused by cancer metastasis, which is the spread of tumour cells to remote parts of the body. But how do cancer cells survive and grow in other parts of the body, sometimes appearing years after the original tumour has been removed?
Scientists over the past decades have largely focused on the cancer cells’ properties, ignoring cells such as those in the immune system. New research shows that the immune system might not be an innocent spectator: rogue immune cells can extinguish the body’s counterattack while others can add fuel to the fire to create an inferno in which the cancer cells thrive.
Our goal is to map how cancer cells work with immune cells to settle in faraway places in the body. We believe that the patients’ own immune cells might be helping the cancer cells under the influence of hormones known as cytokines. These cytokines, released from the cancer cells, might already be furnishing the future metastatic site before the first cancer cell shipment has even left. Almost every person on this planet has an immune system that cancer can exploit, so could we also harness it to fight the invader?
The immune system is a large dynasty of cells interacting with each other and our journey’s first step is to map the family tree. To do this, we will study brain tissue chunks from patients with brain metastases. By looking at genetic information and labelling the immune cells with colourful chemicals, we will understand which immune cells were interacting with the cancer cells in the moment that the surgeon extracted the tissue. Knowing how well the patients eventually did, we can infer which immune cells correlate with a worse outcome.
Once our portfolio of the most important immune cell types is ready, we’ll then turn our attention to how tumour cells manipulate the stock market at metastatic sites. We will use single-cell RNA sequencing, in which a machine captures the active genes in each individual cell, also known as the cell’s transcriptome. If the cell’s genome is a fingerprint, then the transcriptome tells us where the finger is pointing. We will apply this method on tumour cells grown in mice to find cancer cells that are dialling immune cells. We will tap into the gossip being exchanged between cancer and immune cells, to see whether there is any communication that could be potentially censored to silence the manipulative cancer cells.
In conclusion, a new treatment to stop cancer from spreading would greatly benefit cancer patients, and if it were as universal as our immune system, that would be even better. It’s time we view our immune systems not as invincible armies, but as gullible masses during an election campaign, and that we seek new strategies to free them from their misinformation.