MARTINA DI ROCCO

PhD Graduate

PhD program:: XXXIII


supervisor: Simone Martinelli
advisor: Giancarlo Ruocco
co-supervisor: Alessandro Rosa

Thesis title: Caenorhabditis elegans as a biosensor for the early detection of cancer metabolites in urine samples

The discovery of cheap and non-invasive diagnostic strategies for the early detection of cancer is an urgent priority since treatments are more effective if applied early in the course of the disease. Cancer was shown to deeply alter metabolism opening the door to the development of a wide range of diagnostic tools based on the detection of cancer metabolites as early biomarkers in biological fluids. Thanks to their extraordinary sense of smell, dogs and mice were shown to be able to detect small molecular weight organic compounds as cancer biomarkers in urine samples. However, the introduction of mammals into the clinical practice is not a trivial issue for both experimental and ethical concerns. Conversely, small invertebrate organisms may represent a suitable option for the development of new technologies to promptly diagnose solid tumors. Recently, it has been shown that the nematode Caenorhabditis elegans (C. elegans hereafter) displays attraction towards urine samples collected from patients affected by a wide variety of tumors but avoids those from healthy subjects. Aim of my PhD project was to provide a proof of concept for the development of a microfluidic lab-on-chip platform for the early detection of cancer metabolites in women with breast cancer (BC) by using C. elegans as a biosensor. The nematode has a small nervous system composed of only 302 neurons with a completely mapped connectome and a highly developed chemosensory system that enables it to detect a wide variety of volatile and water-soluble cues. Chemotaxis assays confirmed and extended previous data highlighting the ability of the nematode to discriminate between urine samples collected from BC women prior to chemotherapy and healthy subjects, with a sensitivity (i.e., true positive rate) of 78% and a specificity (i.e., true negative rate) of 97%. Of note, the response was shown to be strongly influenced by hormones in fertile women. Specifically, we observed a positive correlation between the chemotaxis index and the FSH, LH and estradiol release preceding ovulation, and the progesterone peak during the luteal phase, indicating the presence of two relatively narrow time windows for sample collection in young women. Behavioral assays performed on animals in which the AWC sensory neurons were genetically ablated demonstrated an essential role of these neurons in sensing cancer odorants. Furthermore, chemotaxis experiments performed on mutant animals knock-out for genes encoding G-protein coupled receptors (GPCRs) expressed in AWC neurons allowed us to identify candidate receptors which are likely to be involved in binding cancer metabolites. CRISPR-Cas9 engineered C. elegans lines have also been generated to assess the contribution of additional AWCs-expressed GPCRs for which knock-out strains were not available to the attractive response towards cancer samples. Chemotactic data were then mirrored by calcium imaging analyses. Finally, gas chromatography/mass spectrometry (GC-MS) analysis identified a number of metabolites showing significant differences in their relative abundances between cancer and control samples, providing a panel of putative molecules responsible for the attractive behavior of the nematode. We finally established the C. elegans preference towards these compounds and found that the nematode shows chemotactic responses to a subset of them. Dissecting the biochemical mechanisms mediating the ability of the nematode to “recognize” cancer metabolites is expected to generate new insights on the identification of relevant biomarkers for the early diagnosis of cancer, cancer metastasis and relapses, one of the major public health challenges of the 21st century.

Research products

11573/1698111 - 2023 - Phenotypic Assessment of Pathogenic Variants in GNAO1 and Response to Caffeine in C. elegans Models of the Disease
Di Rocco, Martina; Galosi, Serena; Follo, Francesca C.; Lanza, Enrico; Folli, Viola; Martire, Alberto; Leuzzi, Vincenzo; Martinelli, Simone - 01a Articolo in rivista
paper: GENES (Basel : Molecular Diversity Preservation International) pp. - - issn: 2073-4425 - wos: WOS:000939907000001 (3) - scopus: 2-s2.0-85148900984 (3)

11573/1705193 - 2023 - GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments
Novelli, Maria; Galosi, Serena; Zorzi, Giovanna; Martinelli, Simone; Capuano, Alessandro; Nardecchia, Francesca; Granata, Tiziana; Pollini, Luca; Di Rocco, Martina; Marras, Carlo Efisio; Nardocci, Nardo; Leuzzi, Vincenzo - 01g Articolo di rassegna (Review)
paper: PARKINSONISM & RELATED DISORDERS (Elsevier Science:Molenwarf 1, 1014 AG Amsterdam The Netherlands:011 31 20 4853597, EMAIL: p.j.bishop@elsevier.com, INTERNET: http://www.elsevier.com, Fax: 011 31 20 4853249) pp. - - issn: 1353-8020 - wos: WOS:001010021100001 (0) - scopus: 2-s2.0-85154532335 (8)

11573/1689252 - 2023 - The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans
Pannone, Luca; Muto, Valentina; Nardecchia, Francesca; Di Rocco, Martina; Marchei, Emilia; Tosato, Federica; Petrini, Stefania; Onorato, Giada; Lanza, Enrico; Bertuccini, Lucia; Manti, Filippo; Folli, Viola; Galosi, Serena; Di Schiavi, Elia; Leuzzi, Vincenzo; Tartaglia, Marco; Martinelli, Simone - 01a Articolo in rivista
paper: FRONTIERS IN MOLECULAR NEUROSCIENCE (Lausanne: Frontiers Research Foundation, 2008-) pp. - - issn: 1662-5099 - wos: WOS:001005651400001 (0) - scopus: 2-s2.0-85162031200 (0)

11573/1617200 - 2022 - Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders
Coppola, S.; Insalaco, A.; Zara, E.; Di Rocco, M.; Marafon, D. P.; Spadaro, F.; Pannone, L.; Farina, L.; Pasquini, L.; Martinelli, S.; De Benedetti, F.; Tartaglia, M. - 01a Articolo in rivista
paper: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (Mosby Year Book Incorporated:6277 Sea Harbor Drive:Orlando, FL 32887:(800)654-2452, (407)345-4000, EMAIL: hhspcs@harcourt.com, INTERNET: http://www.mosby.com, Fax: (407)363-9661, (314)432-1380) pp. - - issn: 0091-6749 - wos: WOS:000828766100025 (17) - scopus: 2-s2.0-85125476806 (16)

11573/1624291 - 2022 - Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia
Di Rocco, Martina; Galosi, Serena; Lanza, Enrico; Tosato, Federica; Caprini, Davide; Folli, Viola; Friedman, Jennifer; Bocchinfuso, Gianfranco; Martire, Alberto; Di Schiavi, Elia; Leuzzi, Vincenzo; Martinelli, Simone - 01a Articolo in rivista
paper: HUMAN MOLECULAR GENETICS ONLINE (Oxford: Oxford University Press.) pp. 929-941 - issn: 1460-2083 - wos: WOS:000790097100001 (26) - scopus: 2-s2.0-85127521846 (25)

11573/1666784 - 2022 - Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling
Galosi, Serena; Pollini, Luca; Novelli, Maria; Bernardi, Katerina; Di Rocco, Martina; Martinelli, Simone; Leuzzi, Vincenzo - 01a Articolo in rivista
paper: FRONTIERS IN NEUROLOGY (Lausanne: Frontiers Research Foundation, 2010-) pp. - - issn: 1664-2295 - wos: WOS:000843322400001 (5) - scopus: 2-s2.0-85136516821 (6)

11573/1661320 - 2022 - Functional variability of novel CDC42 pathogenic variants is associated with phenotypic heterogeneity of neurodevelopmental and immune-hematologic related disorders
Zara, E.; Di Rocco, M.; Pannone, L.; Mosaddeghzadeh, N.; Ahmadian, M. R.; Simone, Martinelli; Tartaglia, M.; Coppola., S. - 04f Poster
conference: XXV Congresso Nazionale SIGU (Società Italiana Genetica Umana). Trieste. 7-9 settembre 2022 (Trieste)
book: XXV Congresso Nazionale SIGU (Società Italiana Genetica Umana) - ()

11573/1661321 - 2022 - Novel de novo CDC42 variants cause variable functional alterations and heterogeneous spectrum of neurodevelopmental and immune-hematologic rare diseases
Zara, Erika; Di Rocco, Martina; Mosaddeghzadeh, Niloufar; Reza Ahmadian, Mohammad; Spadaro, Francesca; Martinelli, Simone; Tartaglia, Marco; Coppola, Simona - 04f Poster
conference: Small G proteins in cellular signalling and disease. Liverpool. 12-15 settembre 2022 (Liverpool)
book: Small G proteins in cellular signalling and disease. Liverpool. 12-15 settembre 2022 - ()

11573/1667883 - 2021 - C. elegans-based chemosensation strategy for the early detection of cancer metabolites in urine samples
Lanza, Enrico; Di Rocco, Martina; Schwartz, Silvia; Caprini, Davide; Milanetti, Edoardo; Ferrarese, Giuseppe; Lonardo, Maria Teresa; Pannone, Luca; Ruocco, Giancarlo; Martinelli, Simone; Folli, Viola - 01a Articolo in rivista
paper: SCIENTIFIC REPORTS (London: Springer Nature London: Nature Publishing Group) pp. - - issn: 2045-2322 - wos: WOS:000691025800022 (9) - scopus: 2-s2.0-85113327650 (10)

11573/1661319 - 2021 - De novo mutations involving the C-terminal tail of CDC42 cause distinct dyshematopoietic and autoinflammatory disorders
Zara, Erika; Insalaco, Antonella; Di Rocco, Martina; Pannone, Luca; Farina, Luciapia; Spadaro, Francesca; Pasquini, Luca; Martinelli, Simone; De Benedetti, Fabrizio; Tartaglia, Marco; Coppola., Simona - 04f Poster
conference: XXIV Congresso Nazionale SIGU (Società Italiana Genetica Umana). Virtual edition. 17-19 novembre 2021 (Virtual edition)
book: XXIV Congresso Nazionale SIGU (Società Italiana Genetica Umana). Virtual edition. 17-19 novembre 2021 - ()

11573/1554965 - 2020 - Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
Motta, M.; Pannone, L.; Pantaleoni, F.; Bocchinfuso, G.; Radio, F. C.; Cecchetti, S.; Ciolfi, A.; Di Rocco, M.; Elting, M. W.; Brilstra, E. H.; Boni, S.; Mazzanti, L.; Tamburrino, F.; Walsh, L.; Payne, K.; Fernandez-Jaen, A.; Ganapathi, M.; Chung, W. K.; Grange, D. K.; Dave-Wala, A.; Reshmi, S. C.; Bartholomew, D. W.; Mouhlas, D.; Carpentieri, G.; Bruselles, A.; Pizzi, S.; Bellacchio, E.; Piceci-Sparascio, F.; Lissewski, C.; Brinkmann, J.; Waclaw, R. R.; Waisfisz, Q.; Van Gassen, K.; Wentzensen, I. M.; Morrow, M. M.; Alvarez, S.; Martinez-Garcia, M.; De Luca, A.; Memo, L.; Zampino, G.; Rossi, C.; Seri, M.; Gelb, B. D.; Zenker, M.; Dallapiccola, B.; Stella, L.; Prada, C. E.; Martinelli, S.; Flex, E.; Tartaglia, M. - 01a Articolo in rivista
paper: AMERICAN JOURNAL OF HUMAN GENETICS (University of Chicago Press:PO Box 37005, Journals Division:Chicago, IL 60637:(877)705-1878, (877)705-1878, (773)753-2247, EMAIL: subscriptions@press.uchicago.edu, INTERNET: http://www.press.uchicago.edu, Fax: (877)705-1879, (773)753-0811) pp. 499-513 - issn: 0002-9297 - wos: WOS:000565899700010 (29) - scopus: 2-s2.0-85089385871 (28)

11573/1349738 - 2019 - Functional characterization of novel germline mutations affecting CDC42 highlighted their differential impact on multiple signaling pathways.
Di Rocco, Martina; Zara, Erika; Pannone, Luca; Farina, Luciapia; Coppola, Simona; Martinelli, Simone; Tartaglia., Marco - 04f Poster
conference: XXII congresso nazionale SIGU (Roma)
book: Abstract Book - ()

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