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Cancer Metabolism and Cachexia (CaMeCa)

Paolo E. Porporato
Paolo E. Porporato PI

Biographical sketch 

Associate Professor in Experimental Biology at the University of Turin, Torino, Italy 

Main group members
Main group members

  • Elisabeth Wyart Post-Doc

  • Erica Mina PhD Student

  • Rita Vacca Research Fellow

  • Ivan Zaggia Research Fellow

  • Roberta Basile Research Fellow

Research activity

 

Tumors are highly energy demanding to support survival and growth in a harsh environment. Hence, they promote nutrient mobilization from the body to support their increased metabolic demand. Ultimately promoting systemic wasting and cachexia. In particular, we are working on the metabolic competitions occurring between skeletal muscle and growing tumor with the aim of breaking the vicious circle which leads to skeletal muscle wasting and tumor growth. Mitochondrial metabolism plays a crucial role in cancer aggressiveness and immune escape, offering a fascinating perspective on the intricate relationship between cancer cells and the immune system. Understanding this connection can provide valuable insights for developing innovative cancer therapies. Cancer cells often outcompete immune cells for essential nutrients, such as glucose and amino acids, within the tumor microenvironment. By hijacking these resources, cancer cells can maintain their energy-intensive metabolism, while immune cells become metabolically compromised and less effective in their antitumor activities. Cancer cells can manipulate mitochondrial metabolism to produce metabolites and signaling molecules that suppress the immune response. For example, cancer cells may release lactate, which not only serves as an energy source but also acidifies the tumor microenvironment, impairing the function of immune cells and promoting their exhaustion. Moreover, the fusion and fission of mitochondria in cancer cells can impact the expression of immune checkpoint molecules, such as PD-L1, which inhibit the activity of immune cells like T cells. Understanding the interplay between mitochondrial metabolism and cancer aggressiveness, as well as immune evasion, has significant therapeutic implications. Alteration in metabolism eventually will lead to cachexia. Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. The Cancer Metabolism and Cachexia (CaMeCa) Lab is focused on the definition of metabolic dependencies occurring in cancer cell, immune landscape and in the host. To this aim, we are working on multiple fronts to address various aspect of this metabolic interactions: The role of altered iron metabolism in regulating skeletal muscle function during tumor growth We discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases. The impact of mitochondrial function and aminoacid metabolism in regulating cancer growth and immune regulation Targeting mitochondrial metabolism in cancer cells represents a promising avenue for treatment. Strategies include inhibiting glycolysis, targeting mitochondrial enzymes, or modulating mitochondrial dynamics to sensitize cancer cells to immune attack. Additionally, combining metabolic therapies with immunotherapies has shown promise in clinical trials. By disrupting cancer cell metabolism and simultaneously bolstering the immune response, these combination therapies have the potential to enhance treatment outcomes and overcome resistance mechanisms.

To this aim, we are working on multiple fronts to address various aspect of this metabolic interactions: i) to study the mitochondrial metabolism of alternative amino acids as central player in the complex web of cancer aggressiveness and immune escape. Expanding our knowledge of these processes will provide opportunities for innovative cancer treatments that will disrupt cancer cell energetics and restore the immune system’s ability to recognize and eliminate malignant cells. This intersection of metabolism and immunology holds great promise in the ongoing battle against cancer; ii) to understand the impact of altered metabolic activities in skeletal muscle on the development of tumor and its aggressiveness.

  • Bando POC-TOINPROVE 
  • Bando POC-LIFFT on the development of proprietary patent Novel BMP modulators and use thereof. 
  • Bando MFAG-AIRC My First AIRC Grant. “Targeting crosstalk between muscle and cancer” (2019-2024), 
  • Fondo Rita Levi-Montalcini 2014 “Understanding and targeting cancer-related muscle atrophy” (2016-2019) 
  • Bando Finalizzata Giovani Ricercatori (2023-26): “NF-Kb positively regulates Fatty Acid Oxidation in cancer cells, which hinders CD8+ T lymphocytes and promotes tumor progression”. PI: Alessio Menga. GR2021-12374957
  • Bando MFAG-AIRC My First AIRC Grant (2021-26): “Dissecting mitochondrial lysine and tryptophan metabolism to target metabolic symbiosis in lung adenocarcinoma”. PI: Alessio Menga MFAG, Rif. 25908
  • Wyart E, Hsu M, Sartori R, Mina E, Rausch V, Pierobon ES, Mezzanotte M, Pezzini C, Bindels LB, Penna F, Lauria A, Filigheddu N, Hirsch E, Martini M, Roetto A, Geninatti-Crich S, Prenen H, Mazzone M, Sandri M, Menga A, and Porporato PE. Iron supplementation is sufficient to rescue cancer-induced muscle wasting and function. EMBO Reports, e53746 (2022) 
  • Wyart E, Reano S, Longo D, Ghigo A, Riganti C, Porporato PE. Metabolic characterization of a new model of PDAC-induced cancer cachexia, Oxid Med Cell Longev. 2018 Feb 26; 
  • Payen VL, Hsu MY, Rädecke KS, Wyart E, Vazeille T, Bouzin C, Porporato PE* Sonveaux P. Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter. Cancer Res 2017;77(20):5591-5601. doi: 10.1158/0008- 5472.CAN-17-0764. *co-last 
  • Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018 Mar;28(3):265-280. 
  • Brisson L, Bański P, Sboarina M, Dethier C, Danhier P, Fontenille MJ, Van Hée VF, Vazeille T, Tardy M, Falces J, Bouzin C, Porporato PE, Frédérick R, Michiels C, Copetti T, Sonveaux P. Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer. Cancer Cell 2016 
  • Porporato PE, Filigheddu N, Reano S, Ferrara M, Angelino E, Gnocchi V, Prodam F, Ronchi G, Fagoone S, Chianale F, Chianale F, Baldanzi G, Sinigaglia F, Surico N, Perroteau I, Smith R, Sun Y, Geuna S, Graziani A. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. J Clin Invest. 2013 Jan 2;123(2):611- 22. 
  • Porporato PE, Payen VL, De Saedeleer CJ, Préat V, Thissen JP, Feron O, Sonveaux P. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis. 2012 Jun 3;15(4):581-92. 
  • Menga A, Favia M, Spera I, Vegliante MC, Gissi R, De Grassi A, Laera L, Campanella A, Gerbino A, Carrà G, Canton M, Loizzi V, Pierri CL, Cormio G, Mazzone M, Castegna A. N-acetylaspartate release by glutaminolysis ovarian cancer cells sustains protumoral macrophages. EMBO Rep. 2021 Jul 14:e51981. doi: 10.15252/embr.202051981. Epub ahead of print. PMID:34260142. 2-s2.0-85109871059 
  • Menga A, Serra M, Todisco S, et al. Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages [published online ahead of print, 2020 Sep 4]. EMBO Mol Med. 2020; e 11210. doi:10.15252/emmm.201911210. 2-s2.0- 85090134974 
  • Palmieri EM, Menga A, Martín-Pérez R, Quinto A, Riera-Domingo C, De Tullio G, Hooper DC, Lamers WH, Ghesquière B, McVicar DW, Guarini A, Mazzone M & Castegna A (2017) Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis. Cell Rep. 20, 1654–1666. 2-s2.0-85027849350 
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