Taniguchi Laboratory

About Our Research

Hypoxia Biology: A Dual- Edge Sword

Although you might think that low oxygen levels are not a normal stimulus for our cells, it is actually quite routine for most tissue to experience periods of low oxygen. In periods when oxygen levels drop, our cells need to be able to activate a powerful adaptive response in order to survive. For instance, when you get a paper cut (ouch!), you get a small wound that bleeds. Since you have cut through some blood vessels, and blood delivers oxygen, the edges of the wound are often in a state of low oxygen, called hypoxia. This hypoxic state stimulates a powerful healing response that helps you seal the wound. In fact, other researchers have found that activating this hypoxic response prior to ischemia (sudden loss of oxygen in any tissue, such as with heart attacks or stroke) actually protects cells from death.

The mechanisms of how hypoxia stimulates healing in tissues is complex, but it drastically alters the growth and metabolism of cells to heal and to simultaneously depend less on oxygen.

Unfortunately, this same biology may also help tumors to thrive. When a tumor gets large enough, it can alter the blood flow to a region of the body and render it hypoxic. This low oxygen environment is unfortunately interpreted by other nearby normal cells to form a cellular complex called stroma, which may help to form a favorable microenvironment. The complex interplay of the hypoxia pathway within the tumor, stroma and normal tissues are crucial in determining the various aspects of clinical outcomes of a tumor, such as metastasis, drug resistance, and responses to chemotherapy and radiation therapy. There is probably no cancer with a more substantive stroma than pancreatic cancer (Erkan et. al., 2012).

Since hypoxia biology can promote healing in normal tissues, but in some cases may promote aggressive tumor behavior, we have sought to selectively promote the healing power of hypoxia in normal tissues. Our lab has accomplished this with small molecule inhibitors of the EGLN family of prolyl hydroxylases. Blocking the function of these proteins stabilizes the hypoxia inducible factors (HIFs) to a greater extent in normal tissues compared to tumors, which results in selective protection from chemotherapy and radiation damage.

We are trying to exploit these techniques to reduce toxicity from cancer treatments. In addition, we can further enhance tumor killing using a technique called stereotactic body radiotherapy (SBRT), which uses advanced image guidance to precisely deliver high doses of radiation to the tumor, but not nearby normal tissues. By combining these two approaches we believe that we can deliver a therapeutic, and potentially curative, dose of radiation to tumors of the pancreas and liver.

Our lab has several translational projects that aim to understand and harness hypoxia biology to our advantage in treating pancreatic cancer, using genetically engineered preclinical models, patient-derived tumor organoids and patient-derived intestinal enteroids.