Revealing the many faces of cancer: Pointillism, heterogeneity, and plasticity
A tumor is a complex ecosystem. Understanding how this ecosystem of different cell types in the tumor microenvironment works is a crucial step toward personalized, effective treatments. Meet the Pointillism 2.0 project of the VIB Grand Challenges Program and some of the insights that have inspired it.
May 16, 2024
Pointillism 2.0: A promise of personalization
Reviving our immune system to recognize and get rid of cancer cells – immunotherapy – promises to reshape how we approach cancer treatment. One of the leading examples of immunotherapy is immune checkpoint blockade (ICB) therapy, which works by blocking so-called ‘immune checkpoint inhibitors’. This removes the brakes on the immune system to help the body recognize and attack cancer cells.
And yet, despite the great promise, hurdles remain in the implementation of immunotherapy, not in the least the variation in patient response. Some people respond really well and their cancer yields to the immune system’s reinvigorated attacks, but in other people, this response is lacking. Knowing who might benefit from what treatment is key for the future of personalized cancer treatments.
Enter the Pointillism project, an initiative supported by the VIB Grand Challenges Program, led by Diether Lambrechts and Chris Marine (VIB-KU Leuven Center for Cancer Biology) and colleagues from KU Leuven and UZ Leuven. The initial Pointillism project, spanning from 2019 to 2022, focused on four distinct cancer types—breast cancer, recurrent cervical carcinoma, head-and-neck cancer, and melanoma.
What set Pointillism 1.0 apart was its pioneering use of single-cell multi-omics profiling within the context of clinical trials. Unlike traditional bulk omics analyses, this approach provided a view of an unprecedented resolution on tumors and their individual cells. Tumor biopsies were collected from patients undergoing ICB therapy before, during, and after treatment, which allowed the researchers to assess potential biomarkers that can indicate how people will respond to treatment.
Fast forward to 2023, and Pointillism 2.0 takes the stage, building on the success of its predecessor. Pointillism 2.0 will expand and validate biomarkers of the previous project, with the aim of identifying patients who will benefit most from ICB treatment, enhancing patient outcomes and healthcare cost-effectiveness. In the different clinical trials in Pointillism 2.0, tissue and blood samples will be collected, the treatment response will be analyzed, and potential biomarkers will be assessed both individually and combined into a high-performance biomarker panel.
The ultimate goal? A simple blood test, based on validated biomarkers, which allows physicians to swiftly determine which cancer patients will respond well to immunotherapy, optimizing treatment strategies and reducing unnecessary interventions.
The changing nature of (our understanding of) cancer
Projects like Pointillism not only have immediate outcomes in terms of applications but also reveal new insights into the very nature of cancer. Positioning the prediction of therapy response within a broader context of tumor heterogeneity and plasticity, as well as the importance of the tumor microenvironment, forces a fundamental rethink on how cancer grows and evolves inside patients’ bodies.
Chris Marine’s lab recently published three major reviews that offer crucial new insights into that protean group of diseases we call cancer.
The story of cancer, as it usually goes, is this: a cell acquires a mutation, then another one, and another. Eventually, this cell turns cancerous and begins to divide until it becomes a tumor. Within this tumor, cells continue to mutate until there are different ‘cell lines’ in the tumor. Finally, a few cells escape and spread through the body in a process called metastasis.
As with many stories, the real version of the cancer story turns out to be more complicated. For example, the emphasis on genetic mechanisms (the mutations) neglects the relevance of non-genetic mechanisms, such as phenotypic plasticity that allows cancer cells to activate different ‘genetic programs’ in response to changes in oxygen or nutrient concentrations. In a first review, published in Nature, Panagiotis Karras from the Marine lab and colleagues highlight how genetic and non-genetic mechanisms interact in driving metastasis.
Panagiotis Karras: “Recent technological advances, for example, single-cell multi-omics, have really helped us to untangle the crosstalk between genetic and non-genetic mechanisms of metastasis. By understanding how the interplay between these factors drives metastasis, we can think about developing innovative avenues for the early detection and inhibition of this lethal process.”
That potential for innovative therapies is the topic of another review in Cancer Discovery. By bringing together recent findings on tumor evolution, it becomes clear that many forces interact in shaping how a tumor develops and spreads. However, this combination of genetic and non-genetic mechanisms differs between patients, which is both challenging and promising for developing truly personalized cancer care.
A final factor to consider is the tumor microenvironment. A tumor quite literally embeds itself in its environment, and this environment changes as a result, much like a newly raised building changes the world around it. For example, building a new industrial complex requires new roads that lead there. In the same way, growing a tumor requires blood vessels to bring nutrients. In fact, cancer cells are fond of places in the body with a lot of blood vessels. The role of this blood vessel environment – the perivascular niche – is the topic of a recent review in Trends in Cancer by Ada Nowasad and colleagues from the Marine lab.
Ada: “Interestingly, cancer stem cells accumulate in the area around blood vessels. This perivascular niche is an important player in cancer cell dissemination and metastatic tumors. Single-cell technologies and spatial approaches provide a deeper understanding of the role of perivascular cells in shaping the tumor ecosystem, and we might take therapeutic advantage of that. For example, disrupting cell-cell communication at the perivascular niche may benefit anti-tumor therapy by interfering with primary and secondary tumor growth.”
The next leap in cancer research and personalized treatments will result from seeing tumors as what they are: complex, living, evolving ecosystems that include – and respond to – their non-cancerous environment. Good thing that humans are great ecosystem engineers...
On 30 - 31 May 2024, VIB organizes the second edition of the 'Recent Insights into Immuno-Oncology' conference in Antwerp. There, experts will present their latest advances, address challenges in the current status of immunotherapy, and discuss new treatment strategies.
Publications
Karras et al. Decoding the interplay between Genetic and Non-Genetic drivers of metastasis. Nature, 2024.
Magnani et al. Cancer evolution: a multifaceted affair. Cancer Discovery, 2024.
Nowasad et al. Perivascular niches: critical hubs in cancer evolution. Trends in Cancer, 2023.
