Understanding and exploiting hard-wired metabolic dependencies of cancer cells during ER stress

Despite its known side-effects, chemotherapy often remains the first line therapy for many cancer patients when alternative approaches cannot outcompete the therapeutic outcome of this established therapy. Yet, many attempts are on the way that try to find more targeted and more effective approaches to improve existing chemotherapies and reduce toxic side effects.
One research area focuses on cancer cell`s metabolism since cancer cells often have a very different metabolism as compared to the corresponding healthy cells. Reasons for this fact are increased proliferation of cancer cells compared to healthy cells, poor vascularization of tumor tissue resulting in improper nutrient and oxygen supply as well as accumulation of metabolic waste products. While the metabolism is very dynamic and flexible, certain metabolic dependencies exist and can become something like an Achilles heel when cells face certain cellular stress conditions (i.e. oxygen deprivation or accumulation of toxic side products). Although cancer cells are often more resistant to such stressful conditions, they do have certain limits. Pushing cancer cells across these limits through specific treatments can help to induce death of these cancer cells, the desired outcome of cancer therapy. Yet, the therapeutic window needs to be big enough to protect healthy cells from death, one of the major challenges in cancer therapy.
Our previous work has uncovered a specific metabolic phenomenon that cancer cells display when facing endoplasmatic reticulum (ER) stress. This ER stress is often induced during chemotherapy. To overcome ER stress, cancer cells need to activate a specific gene program. Our work has revealed that a specific metabolic intervention can prevent the onset of this gene program. Therefore, in our project we want to (i) understand the molecular details that can explain the failure of this ER stress response and (ii) test in how far our identified metabolic intervention can positively impact chemotherapy outcome. Our approach has little to no toxicity and if successful, could be of great benefit for cancer patients that need to undergo chemotherapy.

FNR CORE International (FNRS)
Partner: GIGA Institute, University of Liege