Largest cancer atlas to date brings new treatments for incurable tumors closer

One in two people will develop cancer in their lifetime. In neither case will doctors be able to determine why, perhaps 15 years or more ago, a healthy cell transformed into a pre-cancer; or when that same cell became malignant and ended up triggering the tumor. This almost science-fiction level of detail can be made possible thanks to new three-dimensional cancer atlases, which describe, cell-by-cell, the interior of tumors, the tissue that surrounds them, and the immune system that tries to eliminate them. It is a new dimension in understanding how this complex disease works, and looking for new ways to cure it.

On October 30, three-dimensional atlases of some of the most lethal cancers were published: pancreatic, breast with metastases, colon, kidney, uterus and bile ducts. It is a scientific feat that has taken years of work and that analyzes samples from more than 2,000 patients. The results are part of the Human Tumor Atlas Network, an international project led by the United States that aims to map all known types of tumor, and which is part of the Cancer Moonshot megaproject, the new space race to reduce cancer deaths by half.

The new atlases offer the first three-dimensional visualization of cancer. They also provide the most detailed description to date of not only what each cancer cell looks like, where it is, and what it does, but also how they communicate with each other, and how they relate to the so-called tumour microenvironment — the surrounding tissue that often acts as a barrier to the immune system and cancer treatments. This is the current frontier of research in this field. The results appear in a collection of 12 studies in Nature and other journals from the same publishing group.

“These studies open a new era in cancer research and have the potential to transform our understanding of the disease and its future treatments,” explains geneticist Li Ding, professor of Medicine at Washington University in St. Louis (United States), and co-author of one of the main studies. For the first time, the evolution of cancer in time and space can be studied at different levels of detail, from the activity of genes and other molecules within cells, to how these are organized at the macroscopic level within organs. With this new batch of published data, the largest to date, there are now 14 atlases of 21 different tumor types.

All people are descended from a single cell that multiplies to create a complete organism, made up of some 30 trillion cells. Until recently, it was thought that even a tumor, no matter how large, originates from a single malignant cell. Another of the studies published shows that this is not always the case. Within a tumor there may be several different cells that have initiated the cancer, each with its own genetic profile and aggressiveness. This may explain why treatments are able to eliminate part of a tumor, but not completely eradicate a cancer. The studies have analyzed how different parts of a tumor respond to treatments and what happens when it manages to invade other organs and cause metastasis, which is responsible for 90% of all cancer deaths.

“The behavior of a tumor does not only depend on its genetics,” Ken Lau, a biologist at Vanderbilt University and co-author of another of the papers, explains to this newspaper. “The same thing happens with people, we are not only our genetics, but also our experiences and who we interact with; our environment. This is what we are seeing now thanks to these atlases.”

The hope is that these new analysis techniques will help to understand why an early stage of cancer spreads uncontrollably and kills a patient in just one year, while a more advanced cancer is eventually cured. Until the arrival of cell-by-cell analysis technology in 2013, cancer was studied in its raw form: crushing cells and analyzing the DNA, RNA and proteins present in this soup, which could contain not only malignant cells, but also cells from surrounding tissue and immune cells. This prevented a spatial and three-dimensional view of what a living tumor looks like inside an organ.

Lau’s work focuses on pre-cancerous lesions: groups of cells that collaborate with each other and can end up generating a tumor. One of the logical applications of these new techniques is to understand why in developed countries some digestive tumors, including those of the colon, are diagnosed in increasingly younger people. “There are epidemiological studies that point to the consumption of antibiotics and diet, but we do not know how these factors are integrated at the cellular level. The possibility of studying the changes between a healthy cell and a pre-cancerous one could help us understand what is happening, and even to design prevention strategies in the general population,” he explains.

Another of the works focuses on metastatic breast cancer, an incurable phase of the disease that has been less studied due to the difficulty of obtaining and handling patient samples, explains Aviv Regev, vice president of the pharmaceutical company Genentech and pioneer of cellular atlases of the human body. “Each of these atlases allows us to delve into a type of tumor and relate the evolution of the patient with the changes in the cellular ecosystem of the cancer and its microenvironment,” says the bioinformatician. For Regev, the published data is “fantastic” material for artificial intelligence. “For example,” he explains, “we can train algorithms to create personal profiles of a patient and visualize their tumor in three dimensions from a biopsy.”

The new atlases show that cancer is much more complex than previously thought. Not only is each person's tumor unique, but there are also different cellular structures within each tumor that determine its response to treatments.

“The level of detail in these studies is unprecedented, it seems like a miracle,” acknowledges Fernando Peláez, director of biotechnology at the Spanish National Cancer Research Centre. One of the key contributions of these studies, explains the scientist, is the knowledge of the tumor microenvironment. Until now it was suspected that the tissue surrounding tumors “is not inert”; sometimes it contributes to the destruction of cancer with anti-tumor signals and other times it does just the opposite, promoting tumor growth and deactivating immune system cells. “The beauty of these atlases,” reasons Peláez, is “the level of detail they provide on this point and the large number of samples they cover.” The molecular biologist believes that it is “perfectly plausible” that in the future these analysis techniques will be used in medical settings, just as routine analyses of genes or complete genomes of patients are currently carried out.

Eduard Batlle, head of the colon cancer laboratory at the Barcelona Biomedical Research Institute, highlights: “This new layer of information tells us which cells are resisting treatments and which cells generate metastasis in other organs. Thanks to these atlases, we can identify new nodes of communication between cells that could be cut off with drugs. The other future application would be to identify patients who are at greater risk of their pre-cancerous lesions turning into tumors and develop preventive therapies.” The biochemist believes that this “is the next frontier in cancer research.”

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