Dr Salvatore Papa

I am a Molecular Cell Biologist devoted to bridge the 'translational gap' between basic and clinical research. I have joined the University of Leeds as part of the 250 Great Minds University Programme to lead the Cell Signaling and Cancer Group in the Leeds Institute of Medical Research at St James's, one of the biggest research institutes in the Faculty of Medicine and Health. In 2021 I was promoted to Associate Professor with tenure in the School of Medicine.

I have studied Molecular Biology and received my doctorate in Experimental Medicine from University of L'Aquila in Italy. During my doctoral training, I had the great opportunity to join the laboratory of Professor Guido Franzoso at the Ben May Institute for Cancer Research at University of Chicago in USA where I have studied the molecular mechanisms controlling cell death (also known as apoptosis). A subject that I was very passionate about during my master studies. After completing my postdoctoral studies,  I have started my independent research career first at Imperial College London, and then at the Institute of Hepatology London. I was also apponinted Visiting Professor at 'Sapienza' University of Rome in Italy funded by a Brain-Gain Start-up Grant from the Italian Association for Cancer Research (AIRC).

I am driven by a passionate curiosity to understand the molecular basis of malignant disease to inform the search for clinical solutions. The discovery of novel molecular targets and innovative cancer therapeutics in areas where medical needs are greatest is therefore my primary research focus.  Research expertise is in:

• Solid tumours, especially breast, liver-gastro and brain cancers; 

• Onco-haematology, including lymphoma, leukaemia and especially myeloma.

By using interdisciplinary approaches including pre-clinical, biochemical and structural methods we aim to identify novel targets that are responsible for cancer cell survival, spread and development.

In addition of being an active scientist, I serve as a Receiving Editor of the journal Oncogene (Nature Publishing Group), Academic Editor of PLOS | ONE and Associate Editor for Frontiers in Cell and Developmental Biology to assess the manuscripts, select appropriate reviewers and making final decsion on the acceptance of manuscripts. I also serve on the committee review panels of charitable organizations and governmental agencies granting research funding, including Biotechnology and Biological Sciences Research Council (BBSRC), part of the UK Research and Innovation funding agency investing in science and research.

I gained a first class in Molecular Biology followed by a PhD in Experimental Medicine. My graduate studies were carried out in the Ben May Department for Cancer Research at University of Chicago, USA. I completed my postdoctoral training at Imperial College London, where I became interested in molecualr oncology. After promotion to Senior Research Fellow (Lecturer status) in 2009 sponsored by a Wellcome Trust personal award, I started my independent career as Group Leader at the Institute of Hepatology London. My primary contributions as an Associate Professor at University of Leeds involve the identification and characterization of novel anti-apoptotic factors as potential cancer biomarkers.

During my postgraduate studies, my research efforts have been directed towards the identification and characterization of the downstream effectors of the prosurvival activity of NF-kappaB. My primary focus was to uncover a mechanism by which Gadd45b, a downstream effector of NF-kappaB, blunts JNK signalling. We have identified the MAPKK MKK7/JNKK2 – a specific and essential activator of JNK – as a target of Gadd45b, and in fact, of NF-kappaB itself. Gadd45b associates directly and tightly with MKK7, inhibiting its catalytic activity, and this inhibition is central to the Gadd45b-mediated suppression of TNF-induced JNK signalling and apoptosis (Papa S. et al., Nat Cell Biol 2004; Papa S. et al., J Biol Chem 2007; Papa S. et al., J Clin Invest 2008; Papa S. et al., Biol Chem 2009).

My current research programs focus on understanding basic cellular mechanisms (i.e. DNA transcription and protein post translational modifications), molecules that control complex regulatory pathways (signal transduction, gene regulation, development and differentiation), and the molecular basis for immunity, inflammation and cancer. The serine/threonine c-Jun-N-terminal kinase (JNK) is an important signalling pathway in eukaryotic cells, and has been chosen as model system to investigate the mechanisms of signal transduction. JNK responds to a variety of extracellular stimuli and regulates various cellular events, including the induction of apoptosis induced by reactive oxygen species (ROS), cell proliferation, and resistance to apoptosis. Consistent with the importance of these events in inflammation and tumorigenesis, regulation of JNK signalling is associated with immunity and cancers in humans. JNK1 and JNK2 are the major forms of JNK expressed ubiquitously. The paradigm is that both JNK1 and JNK2 contribute at the same cellular function. However, emerging evidence from our and other studies demonstrate that JNK1 and JNK2 have either distinct or even opposing biological functions, especially in cancer development (Barbarulo et al., Oncogene 2013; Bubici and Papa, Br J Pharmacol 2014). In a recent study published in Nature Communications (Iansante et al., Nat Commun 2015) we demonstrated that cancer cells stimulate the over-production of the protein known as PARP14, which enable cancer cells to use glucose to turbocharge their growth and override the natural check of cell death. Using a combination of genetic and molecular biology approaches, we have also uncovered an intricate link between JNK and cellular metabolism, providing evidence for JNK regulating an inextricable crosstalk between apoptosis and metabolism (Papa S and Bubici C, Mol Cell Oncol 2016).

Aberrant activation of the JNK pathway is a key feature in intrahepatic cholangiocarcinoma (ICC) – a highly aggressive type of liver cancer in urgent need of treatment options – and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and therefore the key downstream effectors of this pathway, remain unknown for their applicability as therapeutic targets. In a seminal publication in HEPATOLOGY (Lepore et al. Hepatology 2021), we have demonstrated that the constitutive activation of JNK leads to elevated levels of PIN1 expression, thus promoting ICC cell proliferation. We show that JNK proteins directly interact with and phosphorylate PIN1 at Ser115. The phosphorylation of PIN1 at this specific residue directly causes the increase in intracellular PIN1 levels by preventing its mono-ubiquitination at Lys117, and, consequently, inhibiting its proteasomal degradation. Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation through PIN1 inhibition. Indeed, we also show the potential application of PIN1 inhibition using all-trans retinoic acid (ATRA) for ICC therapy. 

A full coverage of our recent studies has been discussed at The Conversation UK (2015) The Conversation UK (2021)

Grants and Fellowship as principal investigator:

• 2021–2023    Leukemia & Myeloma Research UK – Project Grant
• 2020–2022    Guts UK – Developmental Grant
• 2020–2022    Rosetrees Trust – Seedcorn awards
• 2018–2021    Blood Cancer UK – Project Grant .
• 2016–2019    University of Leeds – PhD Studentship.
• 2016–2021    250 Great Minds Programme Fellowship, University of Leeds
• 2013–2016    AMMF, the Cholangiocarcinoma Charity – Project Grant.
• 2011–2014    Birkbeck, University of London – PhD Studentship.
• 2011–2014    Foundation for Liver Research – Project Grant.
• 2010              Wellcome Trust & Imperial College London – Value in People Award, bridge funding.
• 2010–2013    Italian Association for Cancer Research (AIRC) – Start-up Grant.

• 2015, Award for Best Oral Presentation – Digestive Disorders Federation, International Meeting DDF 2015, London, UK.
• 2013, Award for Excellence in Basic Science – British Association for the Study of the Liver (BASL), BASL Annual Meeting 2013, London, UK.
• 2009, Cancer Researcher Award Lecture – European Association Cancer Research (EACR), BACR/EACR Symposium: Transcription and Cancer. Cambridge, UK.
• 2008, Grant-in-aid for Meeting Attendance – European Molecular Biology Organization (EMBO), EMBO Workshop: NF-κB Network in Development and Disease. Capri (Naples), Italy.
• 2004, PhD studentship – Italian Ministry of Education, University and Research (MIUR), University of L’Aquila, Department of Experimental Medicine, L’Aquila, Italy.
• 2003, Award for Best Post-Doc Oral Presentation – The University of Chicago, Annual Retreat Meeting, Committee on Immunology, Delaware, WI, USA.
• 1997 – 1998, Undergraduate Studentship – University of L’Aquila, Dean Office, Faculty of Science.
• 1996 – 1997, Undergraduate Studentship – University of L’Aquila, Department of Chemistry and Chemical Engineer, Faculty of Science.
• 1995 – 1996, Undergraduate Studentship – University of L’Aquila, Dean Office, Faculty of Science.

MISSION 
We focus our research on understanding the molecular mechanisms, regulation and role of apoptosis (i.e. programmed cell death) in pathogenesis, and translating these insights in therapeutic concepts and, if possible, novel treatments for human disease including cancer, inflammation and infectious disease.

RESEARCH LINES

In normal tissues, there is a balance between the generation of new cells via cell division and the loss of cells via cell death. Old cells become damaged over time and are eliminated. The classical example include shedding of dead skin cells from the skin that are replaced by newly generated cells.  Like cell division, cell death is also tightly controlled. Hence, cells frequently die by a process termed programmed cell death or apoptosis (a Greek term meaning ‘falling off’, in reference to leaves falling off a tree). In biology, the term apoptosis refers to a form of 'programmed cell death'.

Aberrant apoptosis is critically involved in many debilitating or life-threatening diseases, including cancer, chronic inflammation and neurodegenerative disease. Moreover, inducing apoptosis has become a treatment option for certain cancers but current anti-cancer approaches face problems of intrinsic or acquired resistance that contribute to maintain cell survival.

Our research interests aim to investigate the molecular mechanisms regulating apoptosis in response to mitogenic signals such as pro-inflammatory cytokines and oncogenic stimuli. Specifically, we investigate the link between metabolism, cellular transformation and resistance to apoptosis.

RECENT FINDINGS AND TECHNOLOGICAL APPROACHES

During the last decade, we have devoted our research activity in studying the biological role of NF-kB transcription factors in normal and diseased states, and how alterations of its transcriptional activity contribute to human disease, including autoimmunity, chronic inflammation and cancer.

We have made important contributions to the fields of cell biology and apoptosis and our work has significantly advanced the understanding of the mechanisms by which NF-kB promotes cell survival and proliferation in response to pro-inflammatory signals. We have published seminal studies that spanned from the early gene discovery phase to further mechanistic characterisation and finally to the demonstration of biological relevance in animal models (three major research papers as a first author (De Smaele E et al., Nature 2001; Papa S. et al. Nat Cell Biol 2004; Papa S. et al. J Biol Chem 2007; Papa S. et al. J Clin Invest 2008). These studies have also contributed to the generation of two international patents(WO2003028659 A2 and EP1506784 A1), and are the scientific background behind the generation of novel anti-cancer drugs currently being tested in pre-clinical studies.

In more recent years, we have established a research team focussing on the identification and characterisation of novel kinases substrates. On this regard, our team's research program aims to explore the regulation and function of c-Jun N-terminal Kinase (JNK) and the molecular mechanisms by which each kinase isoform acts in malignant cells. We have recently shown that JNK2 is the only JNK isoform involved in pathogenesis of multiple myeloma, and that the poly(ADP-ribose) polymerase (PARP14), a key regulator of B-cell survival, acts as a specific downstream effector of the JNK2 signal pathway (Barbarulo A et al., Oncogene 2013; Bubici C and Papa S, Br J Pharmacol 2013).

These studies have benefited from a close collaboration with Dr Bubici at Brunel University London. We have further explored the role of the anti-apoptotic protein PARP14 in the regulation of metabolic program (aerobic glycolysis, also known as Warburg effect) in a variety of proliferating cells, including pre-cancerous and cancerous cells. A manuscript reporting these findings has been published in Nature Communications (Iansante et al., 2015). 

Using loss-of-function studies in vitro and in vivo, we have shown that PARP14 is an important determinant of the Warburg effect in most proliferating tumour cells, including hepatoma, breast carcinoma, brain glioma, gastric carcinoma and myeloma. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 (a key glycolytic enzyme) through phosphorylation of Thr365. Using this mechanism, PARP14 suppresses the metabolic activity of PKM2 leading to enhanced glycolysis, and thus demonstrating a link between suppression of apoptosis and altered metabolism in cancer cells. These studies place PARP14 at the centre of a hub regulating energy metabolism and cancer cell survival, making it a possible molecular target in cancer therapy. These mechanistic representations allow functional prediction of the effect of blockage of metabolic pathways in cancer cells via PARP14 inhibition. Pre-clinical validation of the findings is performed using genetic or pharmacological inhibition of PARP14 in in-vitro and in-vivo tumour models.

Lately, we have also focused our attention in human cancers in urgent need of treatment options, such as intrahepatic cholangiocarcinoma (ICC), a form of bile duct cancer. In a major new study published in HEPATOLOGY (Lepore et al., 2021) our research group demonstrates a mechanistic link between JNK activity and ICC cell proliferation through PIN1 protein stabilization and proposes that the drug all-trans retinoic acid (ATRA) could be used to help treat this form of bile duct cancer.

"As you read this, millions of your cells are dying. Don't panic — you won't miss them. Most of them are either superfluous or potentially harmful, so you are better off without them. In fact, your health depends on the judicious use of a certain kind of programmed cell death—apoptosis". If you'd like to read more about these fascinating processes read more here >>

All the cells in our bodies are programmed to die. As they get older, our cells accumulate toxic molecules that make them sick. In response, they eventually break down, clearing the way for new, healthy cells to grow. This “programmed cell death” is a natural and essential part of our wellbeing. Every day, billions of cells die like this in order for the whole organism to continue functioning as it is supposed to.
But as with any programme, errors can occur and injured cells that are supposed to die continue to grow and divide. These damaged cells can eventually become malignant and generate tumours. In order to avoid their programmed cell death in this way, cancer cells reorganise their metabolism so they can cheat death and proliferate indefinitely.

Cancer researchers have known for decades that tumours use a faster metabolism than normal cells in our body. One classic example of this is that cancer cells increase their consumption of glucose to fuel their rapid growth and strike against programmed cell death. This means that limiting glucose consumption in cancer cells is becoming an attractive tool for cancer treatments. In a study published in Nature Communications we showed that cancer cells stimulate the over-production of the protein known as PARP14, enabling them to use glucose to turbocharge their growth and override the natural check of cell death. Using a combination of genetic and molecular biology approaches, we have also demonstrated that inhibiting or reducing levels of PARP14 in cancer cells starves them to death.

The best news is that by comparing cancer tissues (biopsies) from patients that has survived cancer and those that have died, we have found that levels of PARP14 were significantly higher in those patients that have died. This means that levels of PARP14 in cancer tissues could also predict how aggressive the cancer would be and what the chances are of a patient’s survival. This means that a treatment which could block the protein could represent a significant revolution in the future of cancer treatment. What’s more, unlike traditional chemotherapy and radiotherapy, the use of PARP14 inhibitors would only kill cancer cells and not healthy ones. Our work is aimed to design and generate new drugs that can block this protein and work out how to use them safely in patients.

More recently we have also been studying rare types of cancers. Bile duct cancer is a rare but aggressive form of cancer, affecting just over 2,000 people in the UK every year. However, incidences of bile cancer are steadily increasing every year – with some estimating it could one day be as common as breast cancer. In a major new study published in Hepatology our research group proposes that the drug all-trans retinoic acid (ATRA) could be used to help treat bile duct cancer.  ATRA is the active metabolite (small molecule) of vitamin A. ATRA is involved in cell differentiation (where one cell turns into a specific type of cell), and cell death. It’s also used to treat certain types of blood cancers – such as acute promyelocytic leukemia. Although using ATRA to treat this type of leukemia is well established and tolerated in patients, research on its use in solid tumours is limited.

Using pre-clinical models of disease, our research showed that ATRA shrinks tumours by 40% compared to a placebo treatment. ATRA works to reduce the incidence of tumours through specific molecules – such as nuclear retinoic acid receptors, a type of receptor that controls the presence or absence of certain proteins. More recently, it’s been shown that ATRA suppresses the expression and activation of a protein called PIN1, a master regulator of cancer-causing genes and tumour suppressors in tumour cells. Our team showed that PIN1 is abundant in liver biopsies of patients with bile duct tumours. ATRA works to reduce the abundance of PIN1 in cells and animal models of bile duct cancer.

For a news release follow the link