Periodic Reporting for period 2 - PancObese (Metabolic mechanisms underpinning obesity-driven pancreatic cancer)
Periodo di rendicontazione: 2023-03-01 al 2024-08-31
Pancreatic cancer is a highly aggressive malignancy, with an extremely poor survival rate that is due to a lack of strategies for early detection and a very high rate of metastasis. Despite being a relatively rare cancer, pancreatic cancer is now the fourth leading cause of cancer related deaths, with estimates that it will become the second most common cause of cancer mortality by 2030. Current therapies have only limited efficacy and although many studies have analysed the genetic changes that occur in these cancers, this has not led to a breakthrough in treatment. As a result, the median overall survival of patients with pancreatic cancer is only 12 months. In addition to the human cost of pancreatic cancer on patients and their families, hospitalisation, palliative treatment and loss of productivity results in a high economic burden of this cancer on society. It is clear that new treatment options are urgently needed. We believe that the development of effective treatments will depend on a better understanding of the mechanisms that underpin the development and progression of pancreas cancer, beyond identification of genetic changes. The goal of this project is to identify the mechanisms that support the development of pancreatic ductal adenocarcinoma (PDAC) – the most common form of pancreatic cancer. Our approach is focused on the metabolic changes that occur in the cancer cells and the cross talk between the cancer cells and normal tissue. It is well known that the normal cells of the body have a strong influence on cancer progression, and the observation that obesity is linked to increased incidence of PDAC suggests a role for fat tissue (or adipose tissue) in promoting the development of these cancers. Our focus is therefore to understand how adipocytes contribute to PDAC development. Our overall objectives are to reveal new approaches to treat PDAC by targeting the tumour cells themselves, or by interfering with the supporting interactions between the cancer and adipose tissue. Furthermore, as PDAC is usually diagnosed in patients at a late stage, when therapeutic intervention is much more challenging, we also hope to identify new biomarkers for early detection of PDAC development.
PDACs develop in nutrient poor environment and for successful malignant progression, these tumours need to cope with metabolic stress and access nutrients. We have found that one of these mechanisms involves the interaction of cancer cells with adipocytes. Using multiple fractionation protocols and untargeted metabolomics analysis, we identified 27 metabolites produced by adipocytes that work in concert to support PDAC proliferation. The contribution of multiple adipocyte derived metabolites - rather than just one - complicates our ability to effectively target this activity of adipocytes, so we have turned to exploring how these metabolites affect PDAC cells. We have shown that adipocyte produced metabolites can protect cells from undergoing excessive activation of a stress response pathway that would normally arrest proliferation in starvation conditions. Our investigation of the role of mitochondrial ROS in the adipocyte/PDAC interaction has focused on the modulation of TIGAR and serine. This work has shown that – in contrast to other cells - loss of TIGAR does not clearly increase mitochondrial ROS in adipocytes in vitro, although in some models we see an effect of adipocyte TIGAR loss on tumour growth in vivo. This is under further investigation. We have found that adipocytes can be induced to upregulate their ability to produce serine under conditions of serine starvation. This adipocyte produced serine supports the growth of PDAC cells that depend on exogenous serine, in part by providing antioxidant defence. We carried out an analysis of the role of ALDH1L2 and formate in PDAC development, showing that ALDH1L2 is only expressed in pancreatic acinar cells, with loss of expression during the transition to ductal cells. As PDAC tumours are composed of ductal cells, they do not express ALDH1L2. As we showed previously in other cell type, the loss ALDH1L2 expression increases ROS and formate production by PDAC cells. The transition of acinar to ductal cells (or ADM) is important in the response to acute pancreatic damage and the development of PDAC. In acute damage, ADM can be reversed during recovery from damage, and we have found that this process is significantly delayed in mice unable to express ALDH1L2. Initial results are suggesting that failure to resolve the damage response due to the loss of ability to express ALDH1L2 also leads to a more aggressive form of PDAC, with increased metastasis.
While we were hoping to identify a single metabolite responsible for the support of proliferation of PDAC cells, the observation that this is the result of multiple input signals is new and interesting. We are now beginning to reveal the mechanism through which these metabolites function to affect PDAC cells, and unexpectedly have shown that this is through an ability to prevent the excessive activation of a starvation-induced integrated stress response. Further work over the next years will allow us to pin down the exact mechanism through which this rescue functions, with initial results pointing to an iron dependent modulation of hypoxia signalling that potentially involves heme synthesis. Understanding this response will reveal novel points of intervention for therapy. The ability of adipocytes to support the requirements of PDAC cells for serine was also unexpected and has allowed us to look more closely into the mechanisms involved in the response of PDAC cells to serine depletion. A screen for genes that may be important to allow cancer cell survival under conditions of low serine has been performed and validation of interesting targets in PDAC cells is now underway. Identification of proteins that are required for PDAC cell survival under conditions of serine starvation may allow us to develop combinatorial therapeutic responses that inhibit the ability of adipocytes to produce serine along with the inhibition of survival pathways in the PDAC cells themselves. Our previous work demonstrated the therapeutic effect of limiting serine, and new targets identified in the present project are likely to synergise with these approaches. Further analysis of the role of TIGAR and ALDH1L2 in PDAC cells and adipocytes will allow us to understand the contribution of ROS and formate in both cell types to enhanced tumour development. Our preliminary work has shown that the loss of ADLH1L2 expression in PDAC cells leads to an increase in formate production that can be detected in the circulation. We are therefore investigating whether increased serum formate levels could function as an early marker of PDAC development. Although we have not found different activities of adipocytes from lean and obese mice, we will continue to examine the impact of obesity on the cancer-promoting signalling pathways that are being identified.