In cancer treatment, new evidence that the neighborhood matters

The advance of any cancer is determined not only by the molecular characteristics of the tumor itself but also by its interaction with the cells that surround it. Yet understanding how exactly these interactions in the tumor microenvironment influence the course of the disease has been difficult to study.

In a new study, researchers at Yale and University College of London analyzed the molecular interactions that occurred in response to a variety of cancer treatments in more than 2,500 organoids, or lab-produced models of tumors and their microenvironment, derived from the cells of patients with colon cancer.

The researchers were able to identify specific interactions between the tumors and surrounding tissues that can help predict the prognosis for individual cancer patients and inform treatments that would most likely be beneficial to them.

The results were published Dec. 7 in the journal Cell.

“This study helps us understand where tumors start and if treatment drives them towards chemo-resistance and chemo-sensitivity,” said Smita Krishnaswamy, associate professor of genetics and computer science at Yale School of Medicine and co-senior author of the study.

All cancers are molecularly distinct and can range from relatively non-threatening to potentially lethal. Outcomes often depend upon the tumors’ microenvironment, or the cells that surround the cancer. It has been difficult, however, to assess the molecular events that occur during the interactions between tumors and these surrounding cells, and to determine which might lead to a good prognosis or a poor one.

For the new study, the researchers harvested cells from tumors of patients to develop organoids. They then developed a mass cytometry platform that allowed them to measure important molecular clues in the organoids — such as levels of DNA damage, cell cycle activity, and cell death — in response to therapy.

They used a data analysis tool developed in the Krishnaswamy lab called TRELLIS, which allowed them to analyze the organoid’s response to a variety of treatments such as chemotherapy at the level of single cells.

One intriguing result, they found, was that YAP (yes-associated protein) signaling — a key part of the Hippo signaling network, which controls organ growth, that enables cell-to-cell communications — from healthy cells that surround cancer tumors can actually be complicit in protecting tumors from treatments such as chemotherapy. This finding, they say, suggests that therapies that inhibit these signals may be beneficial.

But when they assessed the effect of multiple drug therapies on the organoids, they found that a complete response to treatment — the death of tumor cells themselves — was highly individualized in the organoids. In other words, Krishnaswamy said, different therapies resulted in different outcomes for each organoid tested.

“This tool not only can help assess prognosis for individual cancer patients but also suggest the most effective cancer therapies for them,” she said.

Christopher J. Tape of University College of London is co-senior author of the paper.