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Symposium on heart regeneration 2017

We are organizing a “Symposium on heart regeneration: Direct stimulation of cardiogenesis as a novel strategy for treating heart failure”. The meeting will be held at our institution (Scientific and Technological Pole, IRCCS MultiMedica, Italy) on November 16th 2017. Invited speakers include our collaborators and international leaders in heart regeneration, namely Prof. E.Tzahor (Weizmann Institute, Israel), Prof. J.Bakkers (Hubrecht Institute, The Netherlands) and Prof. Gilbert Weidinger (Ulm University, Germany).

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Our review on the role of CYP1B1 in cancer development is out in Cancer Treatment Reviews!

Abstract: Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.

Highlights:
•CYP1B1 triggers carcinogenesis by activating exogenous and endogenous molecules to reactive species.
•Other CYP1 family members play protecting roles against tumor formation by detoxifying carcinogenic compounds.
•CYP1B1 regulates multiple cell types within the cancer microenvironment, supporting a loop of inflammatory angiogenesis.
•Several chemopreventive phytochemicals are potent and specific CYP1B1 inhibitors.
•Specific CYP1B1 inhibition may translate into clinical chemoprevention/angioprevention approaches.

Go to the full article: D’Uva G, Baci D, Albini A and Noonan DM. Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. Cancer Treatment Reviews, 2017

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D’Uva lab receives ERA-CVD grant award on cardiovascular disease

We are very happy to receive a research grant  “ERA-CVD Call 2016 for Transnational Research Projects on Cardiovascular Diseases” of European Union’s Horizon 2020 Framework Programme. This grant gives us the opportunity to establish our lab in Italy, in IRCCS MultiMedica (Milan)!

The project, in collaboration with Hubrecht Institute (Netherlands), Ulm University (Germany) and Weizmann Institute of Science (Israel), will investigate heart regeneration using a comparative approach between different species.

Ischemic heart disease, such as myocardial infarction, causes a massive loss of cardiomyocytes and leads to the formation of fibrotic scar tissue, resulting in impaired cardiac function and ultimately, heart failure. Recently, it has been demonstrated that myocardium is naturally regenerated in the human heart. However, the rate of replacement is too low to repair large areas of damaged myocardium. Stimulating the very low intrinsic proliferation rate of cardiomyocytes is a promising strategy for cardiac repair in patients with heart failure. To identify such repair signals, this project will use zebrafish, where cardiomyocyte regeneration occurs naturally, and mice, where it does not. Different possible reasons for the difference in the regenerative capacity of lower vertebrate versus mammals will be explored. The goal is to develop regenerative medicine strategies based on endogenous cardiomyocyte capacities.

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Our article on inflammation and cancer resistance to EGFR-targeted therapy is out!

Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A, IL1B and IL8, which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro. This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.

Go to the full article: Gelfo V, Rodia MT, Pucci M, Dall’Ora M, Santi S, Solmi R, Roth L, Lindzen M, Bonafè M, Bertotti A, Caramelli E, Lollini PL, Trusolino L, Yarden Y, D’Uva G* and Lauriola M. A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors. Oncotarget 2016 (*co-last author)

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Our review on steroid hormones and growth factor crosstalk is out in Seminars in Cell & Developmental Biology!

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones (SH) acting through nuclear receptors (NRs), are critical signalling mediators of cellular processes. Deregulations of ERBB and steroid hormone receptors are responsible for several diseases, including cancer, thus demonstrating the central role played by both systems.
This review will summarize and shed light on an emerging crosstalk between these two important receptor families. How this mutual crosstalk is attained, such as through extensive genomic and non-genomic interactions, will be addressed. In light of recent studies, we will describe how steroid hormones are able to fine-tune ERBB feedback loops, thus impacting on cellular output and providing a new key for understanding the complexity of biological processes in physiological or pathological conditions.
In our understanding, the interactions between steroid hormones and RTKs deserve further attention. A system biology approach and advanced technologies for the analysis of RTK-SH crosstalk could lead to major advancements in molecular medicine, providing the basis for new routes of pharmacological intervention in several diseases, including cancer.

Go to the full article: D’Uva G* and Lauriola M*. Towards the emerging crosstalk: ERBB family and steroid hormones. Seminars in Cell & Developmental Biology, 2016 (*co-corresponding authors)

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Our editorial article on cardiac regeneration is out in Cell Cycle!

Heart injuries such as those induced by acute ischemia can lead to heart failure, the most common cardiac ailment and a serious health problem worldwide. This occurs mainly due to the inability of the mammalian heart to regenerate after injury. Developing strategies to boost cardiac regeneration processes in humans is therefore clinically imperative.

Go to the full article: D’Uva G and Tzahor E. The key roles of ERBB2 in cardiac regeneration. Cell Cycle, 2015

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The American Association for Biomedical Research cites us as as an example of successful biomedical research that justifies the essential need for animals in medical research

National Association for Biomedical Research (NABR): The Essential Need for Animals in Medical Research

“Rodent research is creating an exciting horizon for cardiovascular disease treatment. Recent research with rats and mice has alerted scientists to the possibility of using growth factors (ref.21) and stem cells (ref. 22) to regenerate cardiac tissue after a heart attack. […] Human medicine would not be where it is today without the incredible contributions of these small yet mighty animals. […]
Ref. 21: D’Uva G, Aharonov A, Lauriola M, et al. Nat Cell Biol. 2015;17(5):627-38
Ref. 22: Ellison GM, Vicinanza C, Smith AJ, et al. Cell. 2013;154(4):827-42″

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