E75b Special Niches: Pancreas/PDAC

Topic

Pancreatic ductal adenocarcinoma presents the most hostile tumor microenvironment known in oncology, a hostility resulting from a combination of extreme physical factors occurring simultaneously within the tumor itself.

The first factor is that a large portion of the tumor mass consists not of tumor cells themselves, but of cancer-associated fibroblasts—supporting tissue cells that the tumor recruits and transforms to serve its own ends; these cancer-associated fibroblasts can account for more than eighty percent of the total tumor mass.

The second factor is that the interstitial pressure within the tumor—that is, the pressure of the fluid filling the spaces between cells—is the highest among all known solid tumors.

The third factor is that, due to the abundance of cancer-associated fibroblasts and this high interstitial pressure, the tumor accumulates a very high density of collagen; this collagen density reduces the ability of drugs to diffuse into the tumor by a factor of ten to fifty compared to normal tissue. This drug resistance—which is purely physical rather than genetic in origin—largely explains the high mortality rate associated with pancreatic ductal adenocarcinoma.

The tumor simulator makes it possible to quantify, first, how this high interstitial pressure physically blocks the delivery of drugs to the tumor cells. Second, it allows for the quantification of how various strategies that reduce the dense supporting tissue surrounding the tumor—such as drugs that relax the fibrous tissue or others that directly break down one of its gelatinous components, hyaluronic acid—can restore, at least partially, the ability of drugs to diffuse back into the tumor. Thirdly, the simulator allows for the quantification of how severe intratumoral hypoxia—a direct consequence of that elevated interstitial pressure and high collagen density—selects for tumor cell clones carrying specific mutations that confer resistance to programmed cell death, thereby favoring the survival of the most aggressive tumor cells.

It is this combination—a large mass of cancer-associated fibroblasts, extreme interstitial pressure, collagen density that physically blocks drugs, and severe hypoxia that selects for the most resistant clones—that makes pancreatic ductal adenocarcinoma one of the most difficult tumors to treat in oncology, and that justifies why much current research focuses on reducing the physical supporting tissue protecting the tumor, rather than targeting only the tumor cells themselves.

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