Editorial IBSA01 Feb 202417 min read

New Frontiers in cancer and healthy aging

The scientific Forum titled "New Frontiers in Cancer and Healthy Aging," organized by IBSA Foundation for scientific research in collaboration with Università degli studi di Napoli Federico II was held on April 18^th2024 - Church of the Complesso dei SS. Marcellino e Festo.

As aging is an inevitable process, understanding how we can age "healthily" becomes paramount. The Forum aims to address the intricate connections between aging and cancer, shedding light on the mechanisms that contribute to its development.

We had insightful exploration, where expert speakers summarized current knowledge and evaluated the impact of immunology, inflammation, and the microbiome on the treatment and clinical aspects of cancer.

Coffee Break and Lunch was offered to all participants.

Full programme
Scientific Committee
Moderators
Speakers

Ibsa Forum - Napoli Salvatore-Franceschi

Aging is a natural process involving a series of physiological and cellular changes in the human body. While aging is inevitable, it is important to understand how we can age "healthily" and what are the main risk factors that can lead to pathological aging and cancer development.
Aging, in fact, is a significant risk factor for the development of cancer. This phenomenon is due to several factors, including accumulation of genetic mutations, deterioration of the immune system, and cumulative exposure to risk factors.

In fact, cancer and aging are associated with multiple biological changes that are in part closely linked, and older patients have higher cancer rates than younger patients. In this context, a patient's "biological" age becomes more crucial than "chronological" age, although adequate techniques to estimate it are lacking.

Immunosenescence is one of the most damaging consequences associated with aging and is probably the main cause of age-related diseases such as cancer. A functional immune system plays a key role in preventing tumor growth. As aging progresses, however, there is a gradual decline in immune function that can lead to an inadequate immune response against developing cancers due to the accumulation of genetic stress. The composition of the microbiome and its impact on various aspects of health, such as cancer risk, is a pertinent component of healthy living. Because both microbes and cancer cells depend on host resources for survival and replication, an excess of energy and nutrients may contribute to the onset and progression of cancer.

In this forum, we summarized current knowledge on the mechanistic connections between aging and cancer and evaluate the influence of immunology, inflammation, and the microbiome on the treatment and clinical impact of cancer.
This Forum, organized by IBSA Foundation for scientific research in collaboration with the University of Naples Federico II, underscores the importance of interdisciplinary collaboration among healthcare professionals, scholars and experts from various fields to establish aging and cancer medicine as a robust clinical and scientific field at the forefront of "personalized medicine," capable of generating significant public health impact.

Programme

09:00 AM Institutional Greetings
09:30 AM Innate immunity and inflammation as a metanarrative of medicine
Prof. Alberto Mantovani
10:00 AM Inflammaging as the common ground of age-related diseases: the latest developments using artificial intelligence
Prof. Claudio Franceschi
10:30 AM Exercise and stem cell aging: The role of inflammation and myokines in cellular rejuvenation
Prof. Thomas Rando
11:00 AM Coffee Break
11:30 AM The microbiota and the leaky gut during aging
Prof. Maria Rescigno
12:00 AM Is metastasis a Darwinian process?
Prof. Pier Paolo Di Fiore
12:30 AM Genetic mutation model: unveiling the pathogenetic mechanisms of thyroid carcinoma
Prof. Giorgio Stassi
1:00 PM Q&A e conclusions
1:15 PM Lunch & Networking

Scientific Committee

Silvia Misiti – Director of IBSA Foundation for scientific research (Switzerland)

Domenico Salvatore – MD. PhD. Professor of Endocrinology, Dipartimento di Sanità Pubblica Università degli Studi di Napoli "Federico II" (Italy)

Moderators

Gabriella Minchiotti – Research Director, CNR-IGB Institute of Genetics and Biophysics "A. Buzzati-Traverso" (Italy)

Domenico Salvatore – MD. PhD. Professor of Endocrinology, Dipartimento di Sanità Pubblica Università degli Studi di Napoli "Federico II" (Italy) and member of Scientific Board of IBSA Foundation for scientific research (Switzerland)

Andrea Alimonti – Professor of Experimental Oncology at ETH Zürich and at Università della Svizzera Italiana, ERC Investigator, EMBO YIP, Head Molecular Oncology Institute of Oncology Research and member of Scientific Board of IBSA Foundation for scientific research (Switzerland)

Antonio Musarò – Full Professor of Histology, Embryology and Biotechnology, Neuromuscular Research Group, Tissue Engineering Unit at the Sapienza University of Rome (Italy) and member of Scientific Board of IBSA Foundation for scientific research (Switzerland)

Speakers

alberto-mantovani

Alberto Mantovani
IRCCS Istituto Clinico Humanitas, Humanitas University, Milan, Italy

Title: Innate immunity and inflammation as a metanarrative of medicine

Abstract: The innate immune system includes a cellular and a humoral arm and underlies inflammation in its diverse forms. Single cell analysis and spatial transcriptomics have provided new vistas on the complexity and function. Moreover, myeloid cells are a source of fluid phase pattern recognition molecules (ante-antibodies) and, in turn, humoral innate immunity shapes recruitment and function of these cells. Myeloid cells represent tools and targets for innovative therapeutic approaches, complementing current strategies. Immunity and inflammation are a component of diverse diseases, ranging from cancer to neurodegeneration. Thus immunity and inflammation represent a metanarrative of Medicine.

Bio A. Mantovani Alberto Mantovani, MD, is Emeritus Professor of Pathology at the Humanitas University in Milan, Scientific Director of the Istituto Clinico Humanitas and Chair of Inflammation and Therapeutic Innovation, William Harvey Research Institute, Queen Mary University, London, UK. His attention has been focused on molecular mechanisms of innate immunity and inflammation and on the role in the tumor microenvironment and cancer progression of tumor-associated macrophages (TAM). He has contributed to the advancement of knowledge in the field of Immunology formulating new paradigms and identifying new molecules and functions. More recently he focused on COVID-19, contributing to the identification of genetic associations and of a novel severity biomarker.
For his research activity he has received several national and international awards, such as the Triennial OECI Award from the Organization of the European Cancer Institutes, the Robert Koch Award for his contribution to tumor immunology and immunotherapy, the American-Italian Cancer Foundation (AICF) Prize for Excellence in Medicine, the American Association for Cancer Research International Pezcoller Award for Extraordinary Achievement in Cancer Research and, most recently, the CIMT Lifetime Achievement Award. The broad impact of his contributions is testified by citations. As of November 2023 he has over 166,000 citations and an H-index of 185 (Scopus).

Claudio Franceschi

Claudio Franceschi
Prof Emeritus, University of Bologna, Italy and Lobachevsky State University, Nizhny Novgorod, Russia

Title: Inflammaging as the common ground of age-related diseases: the latest developments using artificial intelligence

Abstract: Inflammaging is a general theory of aging and age-related diseases proposed in 2000 which has received a number of citations. Artificial Intelligence (AI) is widely used in aging research and eXplainable Artificial Intelligence (XAI) is a rapidly progressing field of machine learning that allows explaining the predictions of complex models. XAI is especially required in sensitive applications, e.g., in health care, when diagnosis, recommendations and treatment choices might rely on the decisions made by artificial intelligence systems. The benefits of applying XAI to aging and Inflammaging, as well as to the development of personalized "aging clocks", will be illustrated.

Bio C. Franceschi Claudio Franceschi is Professor Emeritus, Alma Mater Studiorum University of Bologna (UNIBO) Italy; Head of Lab Systems Medicine and Healthy Aging, Lobachevsky University, Nizhniy Novgorod, Russia (2018-2023). Full Professor of Immunology at the Universities of Padua (1980-86), Modena (1986-1998) and UNIBO (1998-2013). Since 2018 Editor-in-Chief of “Ageing Research Review” (IF 2023: 13.1); Authors of about 900 papers (98388 citations, h-index: 143, Google Scholar, November 2023) - Keynote lecturer at Gordon Conferences, Keystone Symposia on Molecular Biology, Cold Spring Harbor Symposia, EMBO Courses, European and World Congresses on Aging. Major Research Achievements: i) discovery of important characteristics of immunosenescence in humans; ii) proposal of the “inflammaging” theory of aging; iii) pioneering studies on omics [genetics, epigenetics, proteomics, metabolomics, metagenomics, glycomics) of human aging and longevity (centenarians)]. Coordinator of several European large collaborative projects: PROPAG-AGEING (Aging and Parkinson disease, 2015-2019; 6M€); ADAGE (Alzheimer disease; 2016-2019; 1.3M€); NU-AGE (Mediterranean Diet for the elderly, 2011-2016; 9M€); GEHA (GEnetics of Healthy Aging, 2004-2010; 7.2M€). PI OF THE RUSSIAN MEGAGRANT “DPM-AGEING” Digital Personalized Medicine of Healthy Ageing (2018-2022) funded by Government of Russian Federation at State National Research University "Lobachevsky” of Nizhny Novgorod, Russia.
Partner/WP leader of several EU projects: PROTEOMAGE; RISTOMED; MARK-AGE; MYOAGE; IDEAL; COBRA; MISSION-T2D; HUMAN; MYNEWGUT. INTERNATIONAL AWARDS: August 2008: Laurea Honoris causa in Medicine, Universidad Nacional de Córdoba (Argentina); March 2012: Annual Hayflick Lecturer 2012, University of Alabama at Birmingham's Center for Aging; June 2012: The Oxygen Club of California Award: Aging Research Award; April 2015 IAGG-ER Award of the International Association of Gerontology and Geriatrics of the European Region; September 2017: Schober Prize, Martin Luther University, Halle, Germany; October 2017: Nencki Prize, Polish Academy of Sciences, Nencki Institute, Warsaw, Poland; March 2018: Laurea honoris causa, Université Bordeaux, France; May 2023: Lifetime Achievement Award in Immunology and Aging Research, Montreal, Canada.

Thomas Rando

Thomas Rando
Director of the Broad Stem Cell Research Center, Professor of Neurology and of Molecular, Cell, and Developmental Biology at UCLA and Professor at Stanford University, USA

Title: Exercise and stem cell aging: The role of inflammation and myokines in cellular rejuvenation

Abstract: With age, there is a gradual decline of stem cell functionality in tissues throughout the body. We and others have reported that exercise can restore youthful functions to aged stem cells. Given the well-known benefits of physical activity to promote healthy aging, we tested the effects of exercise on age-related changes in the stem cells and stem cell niches of muscle, brain, and blood. Using single cell RNA sequencing, we have found that there is significant increase in both inflammatory signaling and changes in the resident immune cells in all of the stem cell niches. We are currently examining the factors (myokines) that are induced in muscle in response to exercise and secreted into the blood to promote the systemic beneficial effects of physical activity on aged cells and tissues.

Bio T. Rando Thomas A. Rando, MD, PhD is Director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, where he is also Professor of Neurology and of Molecular, Cell, and Developmental Biology. Dr. Rando received his AB, MD, and PhD degrees from Harvard University and then completed a residency in neurology at UCSF and postdoctoral training at Stanford University. Prior to coming to UCLA in 2021, he had been on the faculty Stanford University School of Medicine in the Department of Neurology and Neurological Sciences. At Stanford, Dr. Rando was the founding Director of the Glenn Center for the Biology of Aging, a member of the Institute for Stem Cell Biology and Regenerative Medicine, founding deputy director of the Stanford Center on Longevity, and Chief of Neurology at the Palo Alto VA Medical Center. Dr. Rando’s research focuses on stem cell biology and the biology of aging. His stem cell work has focused on the regulation of cell fate decisions with a particular interest in stem cell quiescence. He has been a pioneer in the field of systemic factors as regulators of cellular aging beginning with seminal studies done in his laboratory using the technique of heterochronic parabiosis. These studies have formed a foundation of current approaches to epigenetic rejuvenation. He is a scientific founder of Fountain Therapeutics whose mission is to develop therapies for diseases of aging based on these fundamental biological principles. Dr. Rando has received numerous awards including an NIH Director’s Pioneer Award, an Ellison Medical Foundation Senior Scholar Award in Aging, the “Breakthroughs in Gerontology” Award from the American Federation for Aging Research, and a Transformative Research Award from the NIH. He is a Fellow of the American Association for the Advancement of Science, a member of the National Academy of Medicine, and a member of the American Academy of Arts and Sciences.

Maria Rescigno

Maria Rescigno
Full Professor at Humanitas University and Group Leader at Humanitas - Vice scientific Director Humanitas, Milan, Italy

Title: The microbiota and the leaky gut during aging

Abstract: The ‘leaky gut’ is a condition associated with several disorders, including the metabolic syndrome, steatohepatitis, and neurodegenerative disorders. Aging is often associated with a leaky gut, particularly in patients with Alzheimer’s and Parkinson’s disease. Changes in microbiota composition can lead to the development of a leaky gut and to the translocation of bacteria or their constituents into the systemic circulation. The consequences are a generalized state of inflammation which can affect brain permeability.

Bio M. Rescigno Maria Rescigno is full professor, vice-rector and delegate for research at Humanitas University and group leader at Humanitas Research hospital, Milan. She graduated in Biology in 1990 at the University of Milan. From 1991 to 1994 she worked at the University of Cambridge, UK, in the Department of Biochemistry, as a visiting scholar. From 1995 to 1999, she worked at the National Research Council of Milan where she received her PhD in Pharmacology and toxicology in 1999. From 1999 to 2001 she worked at the University of Milano-Bicocca where she specialized in Applied Biotechnology. From 2001 to 2017 she has been the director of the Dendritic cell biology and immunotherapy Unit at the Department of Experimental Oncology at the European Institute of oncology. She was the first to show that dendritic cells actively participate to bacterial uptake in the gut, the existence of a gut vascular barrier that resembles the blood brain barrier and the discovery of a new vascular barrier in the choroid plexus. Her major field of interest is mucosal immunology, the microbiota and the development of new cancer immunotherapy strategies. She authored more than 200 publications in high impact journals including Science, Nature Immunol, Immunity, J. Exp. Med., Science TM. She was elected EMBO young investigator in 2007 and in 2011 EMBO member. In 2008-2013 she was visiting professor at the University of Oslo. She has been the recipient of three ERC grants (starting, proof-of-concept and consolidator). From 2019 she is member of the EMBO council. She seats in the technical and scientific board of several charities, funding agencies and in different companies. She has received several awards including the Avon prize as 'symbolic woman of the city of Milan' (2011), a mention of honor of the Belgian embassy (2022), the Rome prize for business, economics and social affairs (2022) and the De Sanctis prize for social health (2023). In 2016 Maria Rescigno has founded Postbiotica s.r.l. a spin-off of the University of Milan that exploits microbiota-derived metabolites as new pharmaceutical agents. In 2017 Postbiotica has won two competitions: Bioupper (Italy) and MyStart BCN (Spain). H-index: 73

Pierpaolo di Fiore

Pier Paolo Di Fiore
MD PhD, Full Professor of General Pathology and Physiopathology, University of Milan and Director, Novel Diagnostics Program, European Institute of Oncology, Milan, Italy.

Title: Is metastasis a Darwinian process?

Abstract: The traditional view of metastasis is that of a selected phenotype, due to genetic variations that confer a migratory/invasive advantage to a subpopulation of cancer cells. While from a pure evolutionary viewpoint this is a controversial statement (what would be the hypothetical advantage of migrating away from the primary tumor? How can the cell compute a “future” hypothetical advantage), it has represented the basic tenet in the field. Recent advances not only argue against the genetic basis of metastasis, but question whether it represents a selected advantage for the cancer cell. I will argue that, in keeping with Gould’s definition, metastases are a spandrel, i.e., an obligatory consequence of a different advantage-conferring phenotype.

Bio P. Di Fiore Pier Paolo Di Fiore is Director of the Novel Diagnostics Program at the European Institute of Oncology (IEO), Full Professor of General Pathology at the University of Milan and one of the founders of the European School of Molecular Medicine (SEMM). Di Fiore has dedicated his scientific career to deciphering the molecular mechanisms of cellular transformation, with particular emphasis on growth factor receptor signal transduction and attenuation, and more recently on stem cell biology. He has received numerous awards, is an EMBO member, a member of the Academia Europaea, and a member of the Accademia dei Lincei. He sits on several international advisory boards and is Senior Editor of the Journal of Cell Biology and former Associate Editor of Cell. He also holds numerous patents.

Giorgio Stasi

Giorgio Stassi
Full Professor in Medical Laboratory Science and Technology, University of Palermo, Italy

Title: Genetic mutation model: unveiling the pathogenetic mechanisms of thyroid carcinoma.

Abstract: Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. We create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in human embryonic stem cells (hESC)-derived TPCs. Specifically, TPCs harboring BRAFV600E or NRASQ61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs.

Bio G. Stassi Professor Giorgio Stassi MD started his research activity in 1989 as researcher with the Laboratory of Immunological medicine at the Institute of Clinical Medicine of the University of Palermo. In 1997 he started work at the Rangos Research Center (PA) USA, under the supervision of Prof. Trucco and working on the pathogenesis of Diabetes Mellitus. He returns to Italy in 2000 and thanks to a AIRC financing, was able to create a Laboratory of Cellular and Molecular Biology at the Department of experimental Medicine at the University of Palermo. In 2002 he takes position as Head of the Cellular and Molecular Pathophysiology Laboratory at the Department of Surgical and Oncological Sciences of the University of Palermo. In the last years his scientific interest has been focused on the study of the role that cancer stem cells have in the onset and the progression in different tumors of epithelial origin such as colon, breast and thyroid tumors. Recently, Stassi and his collaborators published a series of articles on top journals such as Cell Stem Cell and Nature in which he clarified one of the main mechanisms in regard to the resistance to chemotherapy of the cancer stem cells of the colon and proposing a new strategy for the cure of these tumors. He has brought mechanisms to light that regulate epithelial tumor cells’ survival and resistance to conventional therapy. These results have significantly contributed to cancer research, allowing him to issue a patent that enables the development of innovative cancer therapies. He was appointed one of the first to isolate stem cells from colon and thyroid tumors. The advanced development of this system has ulteriorly confirmed its innovative contribution to cancer research leading to attractive discoveries, which have paved the way to designing new “tailored” and more effective anti-cancer strategies. Recently, he identified CD44v6 as a colon cancer stem cells (CSCs) marker required for the metastatic potential of CSCs. Moreover, he has established that the tumor niche reprograms CD44v6- CRC progenitors in metastatic CD44v6+ stem cells concluding that CD44v6 is an independent negative prognostic marker. He determined that CD44v6 cells are dependent upon the activation of the PI3K/AKT pathway. PI3K promotes the expression of CD44v6 in colorectal cancer progenitors, while its inhibition impairs migration and survival of CD44v6+ CRC cells. On the basis of these results, a clinical trial with available drugs that target the PI3K pathway, has been designed for CRC patients. Moreover, he demonstrated that CD44v6 play a pivotal role in the initiation and progression of thyroid carcinoma forming a complex with tissue Inhibitor of Metalloproteinase 1 (TIMP1) and Matrix metallopeptidase 9 (MMP9) and cooperating with Kisspeptin receptor (KISS1R). These observations were highlighted by exploiting thyroid carcinogenesis in vitro and in vivo models, that he obtained introducing specific genomic alterations in human embryonic stem cells (hESCs) via CRISPR-Cas9 technology, aiming to recapitulate the different TC histotypes. The thyroid tumorigenesis model thus generated made it possible to: identify the cells at the origin of the different histotypes of thyroid carcinoma and to identify two new molecular targets KISS1R and TIMP1, whose dual inhibition can be considered an adjuvant therapeutic option for undifferentiated TCs.