Research Topic

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation.

Research activities

First aim of the present work is to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon and pancreatic cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim is to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism.

Ongoing Studies

a) to evaluate the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon and pancreatic cancer
b)  to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses

5 selected publications

1) Marco Segatto, Raffaella Fittipaldi, Fabrizio Pin, Roberta Sartori, Kyung Dae Ko, Hossein Zare, Claudio Fenizia, Gianpietro Zanchettin, Elisa Sefora Pierobon, Shinji Hatakeyama, Cosimo Sperti, Stefano Merigliano, Marco Sandri,  Panagis Filippakopoulos, Paola Costelli, Vittorio Sartorelli, Giuseppina Caretti. Epigenetic Targeting of Bromodomain Protein BRD4 Counteracts Cancer Cachexia and Prolongs Survival. Nature Communications 2017; 8(1):1707

2) Mohelnikova-Duchonova B, Strouhal O, Hughes DJ, Holcatova I, Oliverius M, Kala Z, Campa D, Rizzato C, Canzian F, Pezzilli R, Talar-Wojnarowska R, Malecka-Panas E, Sperti C, Federico Zambon C, Pedrazzoli S, Fogar P, Milanetto AC, Capurso G, Delle Fave G, Valente R, Gazouli M, Malleo G, Teresa Lawlor R, Strobel O, Hackert T, Giese N, Vodicka P, Vodickova L, Landi S, Tavano F, Gioffreda D, Piepoli A, Pazienza V, Mambrini A, Pedata M, Cantore M, Bambi F, Ermini S, Funel N, Lemstrova R, Soucek P.  SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. Sci Rep. 2017 Mar 8;7:43812

3) Sperti C, Gruppo M, Blandamura S, Valmasoni M, Pozza G, Passuello N, Beltrame V, Moletta L. Para-aortic node involvement is not an independent predictor of survival after resection for pancreatic cancer.World J  Gastroenterol. 2017 Jun 28;23(24):4399-4406

4) Rizzato C, Campa D, Talar-Wojnarowska R, Halloran C, Kupcinskas J, Butturini G, Mohelnikowa-Duchonova B, Sperti C, et al.  Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients. Carcinogenesis 37,  957–964 (2016)

5) Basso D, Fogar P, Falconi M, Fadi E, Sperti C, Frasson C, Greco E, Tamburrino D, Teolato S, Moz S, Bozzato D, Pelloso M, Padoan A, De Franchis G, Gnatta E, Facco M, Zambon CF, Navaglia F, Pasquali C, Basso G, Semenzato G, Pedrazzoli S, Pederzoli P, Plebani M. Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen: role of inhibitory co-stimulatory molecules PDL1 and CTLA4. An in vivo and in vitro study. PLoS One. 2013;8(1):e54824.

People involved:

Prof. Cosimo Sperti, Associate Professor
Prof. Marco Sandri, Full Professor
Prof. Stella Blandamura, Associate Professor
Prof. Daniela Basso, Associate Professor

Group members

Dr. Sandra Zampieri, Research Fellow
Dr. Roberta Sartori, Research Fellow
Dr. Lucia Moletta , Research Fellow