Prostate cancer (PCa) remains a key challenge for men’s health and a significant economic burden on society. Majority of primary prostate tumors are treated successfully by radical prostatectomy or external beam radiotherapy, but tumors can progress to invasive and disseminated disease. Patients with metastatic PCa are treated with androgen deprivation therapy; whereas the initial response is very high, complete remissions are rare and disease progression resumes after a median of 2-3 years. The emergent castration-resistant PCa (CRPC) may respond to recently developed AR inhibitory drugs, but this is also short-lived as resistance develops in a few months after which prognosis is very unfavorable. The basis of androgen deprivation therapy is a large body of research implicating androgen signalling in all phases of PCa. The effects of androgens are mediated by the androgen receptor (AR), an androgen regulated transcription factor. AR signaling is critical to the development and function of the normal prostate, in the progression from primary to metastatic disease, as well as a hallmark of CRPC. The downstream pathways regulated by AR may also be important in the final stage of AR-independent disease. Therefore, discovering mechanisms of AR-driven gene regulation and their downstream effects in tumor cells is imperative. Despite extensive global analyses of AR target gene expression, their functional characterization and relevance in PCa is still limited at present. We have previously identified components of AR signalling and its crosstalk with other signalling pathways, including potential biomarkers and therapeutic targets. In particular, our efforts focus on a few genes cloned in our laboratory, such as the six transmembrane protein of prostate 1 and 2 (STAMP1 and STAMP2, also known as STEAPs), that are AR regulated and/or highly restricted to prostate for expression. We have shown that these proteins are essential for PCa growth and survival and that they impact a number of key cellular signaling pathways. We are currently characterizing these proteins functionally, their interacting partners, and how they steer PCa growth, as well as exploring methods to block their function for potential translational applications. We have also discovered that androgen signalling interfaces with endoplasmic reticulum stress pathways (summarized in the other project description); we now have a major effort in this area to functionally characterize this crosstalk and explore important nodes as potential biomarkers and therapeutic targets in model
The very unfavorable microenvironment of solid tumors with low pH, low oxygen tension, and deficient nutrient supply, as well as oncoprotein action, results in accumulation of misfolded proteins and metabolic disturbances that can signal cell death. Cancer cells have developed the capacity to survive these adverse conditions through precise modulation or ‘hijacking’ of stress pathways in the normal physiology. One central stress signaling pathway that is important in normal physiology and is also involved in disease states is endoplasmic reticulum (ER) stress. When there is undue stress on the normal cell, ER stress protective pathways, collectively termed the Unfolded Protein Response (UPR), are activated to maintain cellular homeostasis. When the chronic ER stress cannot be resolved, UPR instead activates cell death pathways. The cancer cell uses the cytoprotective aspects of the UPR for survival and skillfully steers the ‘double-edged sword’ of UPR. We recently showed that canonical UPR pathways are directly regulated by androgen receptor (AR) signaling in PCa cells and are critical for tumor survival and growth. We found that AR activated the inositol requiring enzyme 1 alpha (IRE1alpha) pathway by directly increasing IRE1alpha gene expression as well as those of IRE1alpha target X-Box Protein 1S (XBP-1S, a major UPR transcription factor) target genes. Consistently, there is strong concordance between AR expression and IRE1alpha pathway mRNA gene expression in multiple large cohorts of human PCa, including in CRPC. Furthermore, genetic targeting of IRE1alpha or XBP-1S, or small molecule (MKC8866) targeting of IRE1alpha, strongly inhibited PCa cell growth in vivo. We have shown that at least part of the mechanism of this is by direct activation of the oncogene c-MYC expression. MKC8866 is now in a Phase 1 Clinical Trial. We have also found that one of the other canonical UPR pathways, protein kinase R- like endoplasmic reticulum kinase (PERK) – Activating Transcription Factor 4 (ATF4) pathway, is regulated by AR signaling and has important roles in PCa growth in vitro and in vivo. We have identified a number of novel ATF4 target genes and have shown that they have important roles in PCa biology in vitro and in vivo. For example, we found that mitochondrial one carbon (m1C) cycle gene expression is activated by ATF4 in PCa cells that may serve as biomarkers or therapeutic targets. In another example, we have shown that the ATF4 target FAM129A serves as a feedback regulator of PERK-ATF4 signaling by divergent effects at different levels of the pathway. To identify the molecular framework for the UPR, we are carrying out genome wide knockout screens followed by molecular and cell biological characterization, as well as computational modeling. We have generated novel UPR reporter cell lines that are facilitating this work. We aim to help establish a comprehensive basic understanding of the UPR as well as exploring the possibility that its important nodes may serve as biomarkers or therapeutic targets in cancer, and perhaps in other diseases as well.
This work aims to contribute to basic understanding of hormone action and stress signaling, as well as identifying novel biomarkers and therapeutic targets for cancer. We are pursuing these goals through two related research foci:
We went on a hiking trip to Sognsvann, our first since the pandemic (not counting a smaller one in the winter). We took the metro (about 10 min from the lab) to the Sognsvann lake and hiked through the forest (approximately 3 hours) up to Holmenkollen. Fahri served us a very nice late lunch at his place and we sat around chatting for a long time. Everyone agreed that we need to do this more often!
Our paper on the modulation of integrated stress response pathway in prostate cancer by STAMP2 is published in American Journal of Cancer Research (2022). AbstractSix Transmembrane Protein of Prostate 2 (STAMP2) is critical for prostate cancer (PCa) growth. We previously showed that STAMP2 regulates the expression of stress induced transcription factor ATF4, which is implicated in starvation-induced autophagy. We therefore investigated whether STAMP2 is involved in the regulation of autophagy in PCa cells. Here we show that STAMP2 suppresses autophagy in PCa cells through modulation of the integrated stress response axis. We also find that STAMP2 regulates mitochondrial respiration. These findings suggest that STAMP2 has significant metabolic effects through mitochondrial function and autophagy, both of which support PCa growth.
We embarked on an exhilarating ski trip to the stunning winter paradise of Hemsedal in Norway. Surrounded by snow-capped peaks and enchanting forests, we relished the thrill of navigating Hemsedal's meticulously groomed slopes. The crisp, mountain air greeted our senses, infusing us with a sense of excitement and adventure. Hemsedal, renowned for its picturesque landscapes and world-class ski slopes, promised an unforgettable journey.As our ski trip to Hemsedal drew to a close, we were filled with a profound sense of gratitude for the unforgettable memories we had forged. The beauty of the snow-laden landscapes, the thrill of conquering new challenges on the slopes, and the warmth of the camaraderie we shared would forever be etched in our hearts. Hemsedal had become more than just a ski destination—it had become a sanctuary of natural beauty, adventure, and cherished moments.
Immersed in the vibrant colors of autumn, we embarked on a captivating hiking expedition to the enchanting destination of Veggli. Nestled amidst Norway's picturesque landscapes, Veggli beckoned us with its serene beauty and bountiful trails, promising a memorable adventure in nature's embrace.
In search of thrilling winter escapades, we eagerly ventured to Korketrekkeren for an exhilarating day of sledding. Nestled in the heart of Norway, Korketrekkeren welcomed us with its renowned toboggan run, a winding track that promised an adrenaline-fueled descent through a winter wonderland. As we embarked on our sleds, the crisp mountain air brushed against our cheeks, heightening our anticipation. With each twist and turn down the icy slope, our laughter resonated through the surrounding hills, intermingling with the joyful cheers of fellow sledding enthusiasts. The snow-covered landscape unfolded before us, revealing panoramic vistas of snow-capped peaks and majestic forests, creating an enchanting backdrop for our thrilling adventure. With hearts racing and spirits soaring, we surrendered ourselves to the sheer exhilaration of the ride, cherishing every moment of the adrenaline rush. Our day in Korketrekkeren became a treasured memory of speed, laughter, and the sheer joy of embracing the winter's embrace in this captivating sledding paradise.
Our paper on the stress-mediated reprogramming of one-carbon cycle in prostate cancer is published in Cancer Research (2021).AbstractThe very unfavorable microenvironment of solid tumors with low pH, low oxygen tension, and deficient nutrient supply, as well as oncoprotein action, results in accumulation of misfolded proteins and metabolic disturbances that can signal cell death. Cancer cells have developed the capacity to survive these adverse conditions through precise modulation or ‘hijacking’ of stress pathways in the normal physiology. One central stress signaling pathway that is important in normal physiology and is also involved in disease states is endoplasmic reticulum (ER) stress. When there is undue stress on the normal cell, ER stress protective pathways, collectively termed the Unfolded Protein Response (UPR), are activated to maintain cellular homeostasis. When the chronic ER stress cannot be resolved, UPR instead activates cell death pathways. The cancer cell uses the cytoprotective aspects of the UPR for survival and skilfully steers the ‘double-edged sword’ of UPR. We recently showed that canonical UPR pathways are directly regulated by androgen receptor (AR) signaling in PCa cells and are critical for tumor survival and growth. We found that AR activated the inositol requiring enzme 1 alpha (IRE1?) pathway by directly increasing IRE1? gene expression as well as those of IRE1? target X-Box Protein 1S (XBP-1S, a major UPR transcription factor) target genes. Consistently, there is strong concordance between AR expression and IRE1? pathway mRNA gene expression in multiple large cohorts of human PCa, including in CRPC. Furthermore, genetic targeting of IRE1? or XBP-1S, or small molecule (MKC8866) targeting of IRE1?, strongly inhibited PCa cell growth in vivo. We have shown that at least part of the mechanism of this is by direct activation of the oncogene c-MYC expression. MKC8866 is now in a Phase 1 Clinical Trial. We have also found that one of the other canonical UPR pathways, protein kinase R- like endoplasmic reticulum kinase (PERK) – Activating Transcription Factor 4 (ATF4) pathway, is regulated by AR signaling and has important roles in PCa growth in vitro and in vivo. We have identified a number of novel ATF4 target genes and have shown that they have important roles in PCa biology in vitro and in vivo. For example, we found that mitochondrial one carbon (m1C) cycle gene expression is activated by ATF4 in PCa cells that may serve as biomarkers or therapeutic targets. In another example, we have shown that the ATF4 target FAM129A serves as a feedback regulator of PERK-ATF4 signaling by divergent effects at different levels of the pathway. To identify the molecular framework for the UPR, we are carrying out genome wide knockout screens followed by molecular and cell biological characterization, as well as computational modeling. We have generated novel UPR reporter cell lines that are facilitating this work. We aim to help establish a comprehensive basic understanding of the UPR as well as exploring the possibility that its important nodes may serve as biomarkers or therapeutic targets in cancer, and perhaps in other diseases as well.
Our paper on the regulation of STAMP2 expression in prostate cancer cells by cytokines is published in Cancers (2021).AbstractInflammatory events and dysregulated cytokine expression are implicated in prostate cancer (PCa), but the underlying molecular mechanisms are poorly understood at present. We have previously identified six transmembrane protein of the prostate 2 (STAMP2, also known as STEAP4) as an androgen-regulated gene, as well as a key regulator of PCa growth and survival. STAMP2 is also regulated by, and participates in, inflammatory signaling in other tissues and pathologies. Here, we show that the proinflammatory cytokines interleukin 6 (IL-6) and Interleukin 1 beta (IL-1?) significantly increase and strongly synergize in promoting STAMP2 expression in PCa cells. The two cytokines increase androgen-induced STAMP2 expression, but not expression of other known androgen target genes, suggesting a unique interplay of androgens and cytokines in regulating STAMP2 expression. Interestingly, STAMP2 knockdown significantly increased the ability of IL-6 and IL-1? to inhibit PCa cell growth in vitro. These results suggest that STAMP2 may represent a unique node through which inflammatory events mediate their effects on PCa growth and survival.
Our review paper on the role of the Unfolded Protein Response and hormone-regulated cancers is now published in Trends in Cancer (2020).AbstractCancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.
Our study on the role of PERK-eIF2a-ATF4 signaling in prostate cancer is now published in Oncogene.AbstractCancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2? in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.Link to the paper
Our article on the link between ER stress, inflammation and STAMP2 expression/function is now published in Metabolism (2019).Abstract:BACKGROUND:Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress.METHODS:3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNF?. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays.RESULTS:ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNF? had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBP?-mediated STAMP2 expression.CONCLUSION:These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.
Our study on the importance and mechanisms of endoplasmic reticulum stress signaling in prostate cancer is published in Nature Communications (2019).AbstractActivation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1? RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1?-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1?-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.
We embarked on an invigorating hiking trip to the mesmerizing Kolsåstoppen. We set off early in the morning under a misty, cloudy sky that added an element of mystery to our journey. The air was cool and fresh, infusing our hike with an invigorating energy. As we ventured along the trails, we were enveloped by a cloak of clouds, creating a captivating atmosphere as we moved amidst the vibrant greenery.Despite the overcast weather, our spirits remained high. The ascent was challenging, yet immensely rewarding. As we reached the top, an awe-inspiring view unfolded before us. We had ascended above the cloud cover, finding ourselves in a serene world with a breathtaking panorama stretching out below. The sight of the cloud-kissed valley below was a truly humbling experience, reminding us of the beauty and grandeur of nature. This memorable hiking trip to Kolsåstoppen certainly left an indelible impression on all of us.
We bid farewell to dear Zeynep, who has been an invaluable member of the Saatcioglu Lab. Zeynep was originally a PhD student in our lab a few years ago working on the kinetics of steroid receptor–chromatin interactions. Upon finishing her PhD, she pursued postdoctoral work in Oslo and Germany and returned to Oslo. She then decided to get an education in informatics and obtained a degree this past summer from Oslo Metropolitan University. Congratulations Zeynep! During her time as an IT student, she again joined our laboratory as a part-time research assistant. During her time with us, Zeynep effortlessly balanced her responsibilities (as always, delivering more than the requirement) while pursuing her studies in software engineering. She has also been the gardener supreme of our plants in the lab! Her dedication to both the field of science and technology exemplifies her passion for learning and innovation. We will greatly miss her positive, vibrant presence in the lab. Dear Zeynep, as you embark on this new journey, remember that the Saatcioglu Lab family will always be there cheering you on. Thank you for your dedication, hard work, smile, delicious cakes, and the memories we've shared. We wish you all success and fulfillment in all your future endeavors!
Yesterday was a big day for Bilal and our lab: Bilal had his PhD thesis defense with opponents Prof. Eric Chevet from INSERM, France, and Prof. Peter Nelson from Fred Hutch Cancer Center, University of Washington, USA, examining him. First, Bilal successfully gave the trial lecture on the topic "The role of DNA repair processes in cancer and implications for treatment" with animated discussions on the topic afterwards. It was then the thesis defense with the title "Molecular characterization of the unfolded protein response and implications for prostate cancer". There were very stimulating discussions during the defense with new research ideas emerging where Bilal stood his ground very well and successfully finished his PhD.Congratulations Dr. Bilal Unal!
We are glad to announce the launch of GeneSetR! Utilizing the richness of the latest Genome-wide Perturb-Seq (GWPS) data, GeneSetR presents a user-friendly platform tailored for analyzing and interpreting user-defined gene lists. Try it now, and check our preprint!
We had our traditional Christmas/New Year’s party at Fahri’s place! Good food, music from around the world, and a lot of laughter!
Our MSc student Julia Wilhelmine Klüwer successfully finished her degree with the highest marks! Julia, it has been a great pleasure to have you in our laboratory. You have done such good work, got some very interesting data that require follow-up, and added so much to the atmosphere in our group! We wish you the very best in your scientific endeavors and life in general! All the best, FS Lab
Big shout-out to Lars Jørgen Tvenge Granerud, who just rocked his MSc and graduated with an A! Lars has been a star student from the start, and we're so proud of his accomplishments. We can't wait to see what amazing things he does next. Congrats, Lars! ????
