Why are pancreatic tumors so resistant to treatment? One reason is that the “wound”–like tissue that surrounds the tumors, called stroma, is much more dense than stromal tissue surrounding other, more treatable tumor types. Stromal tissue is believed to contain factors that aid tumor survival and growth. Importantly, in pancreatic cancer, its density is thought to be a factor in preventing cancer–killing drugs from reaching the tumor.

“These conflicting results suggested to us that we still did not know enough about the stroma,” says Daniel Öhlund, MD, PhD, co–first author with graduate student Abram Handly–Santana, postdoc Giulia Biffi PhD, and postdoc Ela Elyada PhD, of the team’s paper, published online in the Journal of Experimental Medicine.

Stroma in PDA becomes what scientists call “desmoplastic.” Its dense, fibrous texture which presents a formidable barrier surrounding a tumor consists of structure–providing connective tissue; cells called fibroblasts which produce the main part of this connective tissue; and a plethora of immune cell types drawn to the tumor site as well as cells that form blood vessels, which bring nutrients to the tumor.

Tuveson’s team capitalized on a technology he and colleagues co–developed with scientists Sylvia Fernandez–Boj and Hans Clevers several years ago: the ability to grow cultures of pancreatic tumors – sampled from people and mice – that develop in a 3–dimensional medium. Called pancreatic organoids, these small spheres mimic the biology of the tumor samples from which they are derived, and thus are a valuable aid for researchers trying to learn more about tumor biology and testing new combinations of treatments on them.

In the experiments organoid technology is taken to a new level, in which organoids derived from tumors are for the first time “co–cultured” with one component of the stroma in which actual tumors grow. The result is a more realistic rendering of what happens in the pancreas of cancer patients—and yet, in a stripped–down, simplified way, such that the effect of adding a single new factor, in this case from stroma, can be clearly parsed.

Fibroblasts form part of the stroma and are typically non–cancerous, but contribute to the cancer’s development by secreting, among other factors, structure–providing molecules to the stroma. But that is only one of their functions. Experiments led by Öhlund and team in human– and mouse tumor–derived organoids, demonstrated something not previously known: fibroblasts come in at least two varieties in PDA, and possibly more.

One subtype of fibroblast noted by Tuveson’s team was distinguished by its production of high levels of a protein called alpha smooth muscle actin, or alphaSMA. Öhlund discovered that the fibroblasts producing alphaSMA were immediately adjacent to neoplastic tumor cells in human and mouse tumor tissue. This result was subsequently observed in PDA organoids grown as co–cultures with fibroblasts. Furthermore, the team noticed that this co–culture resulted in the formation of desmoplastic stroma.

Handly–Santana discovered that a second fibroblast subtype was distinct from others due to production and secretion of the immune–response modulating factor Interleukin 6 (IL–6). In contrast to the alphaSMA–expressing fibroblasts, the IL–6–secreting fibroblasts were found to be more distant from cancer cells in human and mouse PDA tumors, and organoid co–cultures, and did not express elevated amounts of alphaSMA. IL–6 has also been linked to cancer cell proliferation and the process of cachexia, a muscle wasting syndrome that causes weakness and immune suppression in many pancreatic cancer patients.