Solving the puzzle of cancer-associated fibroblasts

Lung cancer cell (Anne Weston, Wellcome Images)

October 27, 2022

By Christopher Vaughan

Solid cancer tumors are hard lumps in our soft tissues because they are usually encased in and permeated with fibroblasts, the cells that make up scar tissue. In fact, even though cancer-associated fibroblasts (CAFs) are an integral part of solid tumors and are thought play a role in cancer’s growth, that role is little understood.

Now a group of Stanford researchers have created a thorough portrait of CAFs’ transcriptomic, epigenomic, and proteomic activity, leading them to conclude that there are actually three types of CAFs and that each reacts to cancer treatments in predictable ways that can affect treatment outcomes. 

“We know that the environment around cancer cells can have a large influence on how cancer grows and responds to therapy,” says institute researcher Michael Longaker, MD. “Cancer associate fibroblasts make up a large part of the tumor environment, but very few cancer treatments take their effects into account.” Longaker is the Dean P. and Louise Mitchell Professor in the Department of Surgery. 

Part of the reason for that, the researchers say, is that there are mixed results about whether CAFs are good or bad actors. Sometimes CAFs can actively promote tumor proliferation, invasion and spread, but at other times, disrupting CAF activity can accelerate tumor progression. Now Longaker, along with Jeffrey Norton, MD, Howard Chang, MD, PhD and colleagues have created a clearer picture of how CAFs are acting in and around cancer. The researchers recently published their work in the journal Cancer Cell. Norton is the Robert L. and Mary Ellenburg Professor of Surgery, and Chang is the Virginia and DK Ludwig Professor of Cancer Research. 

The researchers now see clearly that CAFs come in three varieties—one that is immunologically driven, one that is mechanically driven and a third type that can transition between these other two types, they say. One striking feature of these categories is that they are pretty much the same throughout evolution and throughout the body. “What’s really surprising from an evolutionary standpoint is that across species–from mouse to man–and across tumor types–from breast to pancreas­–this pattern is conserved,” Longaker says. This is true despite the fact that most cells in different kinds of tumors can be very different. 

The immunologically driven CAF is both “inward” looking, interacting with the immunological environment in the tumor, as well as “outward” looking, affecting the action of the immune system generally. “Cancer tumors affect the body’s immune system, and this may be done through CAFs,” says Norton. Mechanosensory fibroblasts, on the other hand, exert an effect on other cells in reaction to physical stresses between cells and tissues. In previous work, Longaker and his colleagues showed that mechanosensory properties in fibroblasts determined whether healing skin formed scars or not. In the tumor, the scientists say, CAFs under physical strain might for example aid the construction of new blood vessels to help feed a growing tumor. 

The third “steady-state” type of CAF is not inherently immunomodulatory or mechanosensory, but may be poised to become one of those types, depending on the situation. The researchers found that this tripartite arrangement can explain some of the seemingly contradictory findings showing that sometimes CAFs promote cancer and sometimes they don’t. “We found that when you use immunotherapy against advanced skin cancer, for instance, it decreases the prevalence of immune-regulating CAFs, but there appears to be a compensatory transition of some steady-state CAFs switching to a mechano-sensory type,” said postdoctoral fellow Michael Januszyk, MD PhD, one of the co-first authors on the Cancer Cell paper. The increase in mechanosensory CAFs might frustrate immunotherapy by prompting changes that make a tumor grow faster even as it is attacked by the immunotherapy, he said.

On the whole, the research supports the idea that CAFs are not just passive but are active components of cancerous tumors that should be taken into account when considering any therapy. 

“For the past 50 years we have been developing new therapies to hit cancer cells, but now we are saying that we should also consider targeting the cells that surround and interact with the cancer,” Longaker says.

The scientists credit their discoveries in part to the tremendous variety of expertise that the researchers brought to the problem. “We are able to have a big impact by leveraging experience in stem cell biology, cancer biology, genomics and proteomics,” says Januszyk. “These discoveries were only possible because we used all these technologies together and pursued multiple heterogeneous modes of investigation.”