Jacco van Rheenen will receive a Jozef Steiner Award (approx. 1 million euro) to film the birth of intestinal tumors and study the influence of diet on the cellular protection mechanisms that eliminate tumor-initiating cells.
Colorectal cancer has become one of the most common types of cancer, and its incidence and prognosis has been linked to factors including age and life-style towards calorie-rich diets. Colorectal tumors are thought to be derived from stem cells that have lost the tumor suppressor gene APC (APC-negative cells). Nevertheless, not every stem cell that loses APC (APC-negative cells) will function as a tumor-initiating cell, since intestinal tissues contain cellular protection mechanisms that can eliminate potential tumor-initiating cells.
Since calorie intake has been linked to tumor incidence and has been shown to severely influence the cellular composition of intestinal tissues (e.g. more stem cells upon a calorie-rich diet), van Rheenen hypothesizes that an altered cellular composition of intestinal tissue (e.g. due to calorie-rich diet) changes the cellular protection mechanisms and therefore the ability of APC-negative cells to initiate intestinal tumors.
Over the years, Jacco van Rheenen and his group of PhD’s, postdocs, analists and students have developed unique intravital imaging techniques to visualize individual cells and their progeny at subcellular resolution over multiple weeks in living mice. In prelimanary experiments, they used this technology to film the behavior and fate of APC-negative cells in a transgenic mouse model where loss of APC is accompanied by a gain of a red fluorophore (so all APC-negative cells are red and vice versa).
By filming and characterizing all APC-negative cells that escape from the cellular protection mechanisms he can explore whether and how the escape of APC-negative cells from the cellular protection mechanisms can be manipulated by dietary- or chemically-induced changes in the celluar composition of intestinal tissue. Also, he can explore the molecular mechanisms underlying the (escape from) cellular protection mechanisms (by APC-negative cells) under normal and altered diets.
Aside from characterizing the cellular protection mechanisms that are present in intestinal tissue to eliminate tumor-initiating cells for the first time, he also hopes to be able to influence these protection mechanisms; how they can be used to decrease the incidence of cancer. Finally the experiments will identify drug targets and potentially drugs treatments that mimic dietary changes preventing the initiation of intestinal cancer.
In the video below you can see an animation of the development of the intestinal crypt by stem cells and the effect of APC-negative cells: