Geir Bjørkøy was central for the identification of the molecular mechanisms for selective autophagy and the first autophagy cargo receptors (p62/SQSTM1 and NBR1). Since then, the group at NTNU has focused on how local signaling and metabolite levels regulate autophagy to control inflammation and tumor development.

Tumors and Autophagy

Progression of solid tumors are influenced by the local immune microenvironment. So-called immunologically “cold” tumors display clear signs of local immune suppression, develop more aggressively, and respond poorly to treatment. On the other side, immunologically “hot” tumors show favorable prognosis and better responses to therapy. We, and many others, aim to find new ways to convert the local immune environment in solid tumors from “cold” to “hot”. Autophagy can be highly selective in the degradation of intracellular proteins and organelles. Thus, autophagy has the potential to change the composition of intracellular signaling proteins in cancer and immune cells as well as other cells within and outside tumors. Activation of the Type I interferon response is a sign of a “hot” tumor. We have published that autophagy coincide with a dampening of the Type I interferon response in innate immune cells. We now study if immune reactions within solid tumors is controlled by autophagy. For these studies, we combine data from tumors from an immunocompetent mouse model with data mining in large databases of tumor biopsy and clinical information. The aim is to explore the idea that autophagy is a selective cellular mechanism that controls tumor immunity.

Innate immune cells like macrophages and neutrophils are important in solid tumors to orchestrate if the microenvironment is “hot” or “cold”. Tumors dominated by anti-inflammatory macrophages indicate poor prognosis and limited effect of therapy. Formation of such macrophages depends on the macrophage specific receptor CSF1R. In a multidisciplinary collaboration, we are screening novel CSF1R inhibitors designed and synthesized by our collaborators at NTNU. The novel compounds are monitored for effects on macrophages in culture, tumors, and tissues. The aim of these studies is to find different ways to target innate immune cells and reprogram the local immune microenvironment.

We also study the interplay between autophagy, tumor immunity and the oxidative stress defense controlled by the transcriptional regulator NRF2. Particularly, we have investigated the role of NRF2-driven transcription in metastatic breast cancer development in mice and humans. This have resulted in the identification of an NRF2-driven gene expression signature in RNA isolated from breast cancer biopsies. The signature is a strong and independent predictor for poor prognosis and has the potential to improve personalized breast cancer treatment.

Autophagy is a core process to mobilize nutrients during starvation. The proliferation of the cancer cells in solid tumors is restricted by the availability of nutrients and oxygen. Many cancer patients develop severe loss of body mass in the terminal phase of the disease. This detrimental complication has been named cancer cachexia and involve severe loss of muscle proteins. It has for long been assumed that the induced catabolism is due to signaling compounds released from the tumor that induce a systemic protein degradation, particularly in muscle cells. However, the identity of such compounds is not completely clear and it is still unknown how the cells induce protein degradation.

We have found that serum from cancer patients contain autophagy-inducing bioactivity and that this activity associates with loss in body weight. Our data demonstrate that IL-6 secreted from cancer cells induce responses in muscle cells when complexed to soluble IL-6 receptor. We have recently uncovered how TGF-related signaling inside tumors controls IL-6 secretion from the cancer cells and weight loss in tumor-bearing mice. We are now studying the interplay between cancer cells, innate immune cells and muscle cells that leads to severe protein degradation and muscle atrophy in cachexia patients. The aim is to find novel therapeutic ways to block this detrimental route for feeding the cancer cell growth.

Collaborators

The group collaborate closely with other groups at CEMIR, NTNU, St. Olavs Hospital and SINTEF. We also collaborate with Professor Terje Johansen at the University of Tromsø and Dr. Carsten Jacobi at Novartis, Basel, on aspects of autophagy and cachexia. For novel compounds targeting macrophage activities, we collaborate with Dr. Clare Pridans at the University of Edinburgh and the Max Planck Lead Drug Discovery Center in Dortmund with manager Dr. Bert Klebel.