Stromal/tumor cells dialogue and metabolic reprogramming in pancreatic cancer

The Tomasini/Vasseur team is part of the COMET department

The team “Stromal/tumor cells dialogue and metabolic reprogramming in pancreatic cancer” (DISARM PDAC) studies the impact of intra-tumoral microenvironment and metabolic reprogramming in pancreatic cancers aggressiveness and therapeutic resistance.

Pancreatic ductal adenocarcinoma (PDAC) represents, with the fourth leading cause of cancer-related death worldwide and a 5-year survival rate of 12%, a challenging public health issue. At diagnosis, 80% of PDAC patients present a metastatic and unresectable disease, with a poor response to classical therapies which makes metastasis to distant organs the determinant of PDA outcome. Surprisingly, while combinatory chemotherapeutic protocols, such as FOLFIRINOX, improved life expectancy for some PDAC patients, the rise of immunotherapy in cancer did not lead to further refinement of PDAC patients’ management.

One could argue that such negative picture relies mainly on two interconnected specific traits of PDAC;

1/ its specific cellular composition in which epithelial tumor cells (TCs) are embedded in a highly fibrotic tumor microenvironment (TME) and outnumbered by several non-tumoral cell types (stromal cells) such as cancer-associated fibroblasts (CAFs), immune cells as well as endothelial and nerve cells, favoring an immunosuppressive ecosystem and

2/ the poor perfusion of TCs with oxygen and nutrients, due to a low vascularization of the tumor, which forces tumor and stromal cells to metabolically adapt to these stringent microenvironmental conditions.

In regards with such statements, and due to the expertise of our team members, we are focusing our projects on 3 axes, including sub-axes:

1. Impact of Stromal/tumor cell crosstalk on PDAC aggressiveness
   – Impact of extra-cellular vesicles in therapeutic resistance
   – Epigenetic and onco-immunology
   – Impact of extra-cellular vesicles in vascular and nervous reprogramming

2.  Metabolic adaptation of PDAC tumor cells
   – Targeting amino acid promoting PDAC aggressiveness
   – PDAC metastases and hepatocytes metabolic crosstalk
   – Role of cPLA2 in PDAC growth
   – Chronotherapies and metabolic drugs

3.  Impact of the stroma on metabolic flexibility/plasticity of tumor cells
   – Biochemistry and biomechanics of ECM in tumoral metabolism
   – Targeting the metabolic stromal/tumor cell crosstalk in chemoresistance

Keywords

• Inter-cellular Dialogue
• Intra-tumoral microenvironment
• Metabolism
• Onco-immunology
• Clinical tools

Main recent publications

• Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer. Hussain Z, Bertran T, Finetti P, Lohmann E, Mamessier E, Bidaut G, Bertucci F, Rego M, Tomasini R. Cell Commun Signal. 2024 Jan 2;22(1):1.
• SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer. Rapetti-Mauss R, Nigri J, Berenguier C, Finetti P, Tubiana SS, Labrum B, Allegrini B, Pellissier B, Efthymiou G, Hussain Z, Bousquet C, Dusetti N, Bertucci F, Guizouarn H, Melnyk P, Borgese F, Tomasini R, Soriani O. Gut. 2023 Apr;72(4):722-735.
• Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance. Vasseur S, Guillaumond F.
  Oncogenesis. 2022 Aug 9;11(1):46.
• TET2 regulates immune tolerance in chronically activated mast cells. Rigo R, Chelbi R, Agopian J, Letard S, Griffon A, Ghamlouch H, Vernerey J, Ladopoulos V, Voisset E, De Sepulveda P, Guittard G, Nunès JA, Bidaut G, Göttgens B, Weber M, Bernard OA, Dubreuil P, Soucie E.
  JCI Insight. 2022 Apr 8;7(7):e154191.
• CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness. Nigri J, Leca J, Tubiana SS, Finetti P, Guillaumond F, Martinez S, Lac S, Iovanna JL, Audebert S, Camoin L, Vasseur S, Bertucci F, Tomasini R.
  Sci Signal. 2022 Aug 2;15(745):eabg8191.
• Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer. Guillot J, Dominici C, Lucchesi A, Nguyen HTT, Puget A, Hocine M, Rangel-Sosa MM, Simic M, Nigri J, Guillaumond F, Bigonnet M, Dusetti N, Perrot J, Lopez J, Etzerodt A, Lawrence T, Pudlo P, Hubert F, Scoazec JY, van de Pavert SA, Tomasini R, Chauvet S, Mann F. Nat Commun. 2022 Apr 13;13(1):1985.
• Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression. Gouirand V, Gicquel T, Lien EC, Jaune-Pons E, Da Costa Q, Finetti P, Metay E, Duluc C, Mayers JR, Audebert S, Camoin L, Borge L, Rubis M, Leca J, Nigri J, Bertucci F, Dusetti N, Iovanna JL, Tomasini R, Bidaut G, Guillaumond F, Vander Heiden MG, Vasseur S. EMBO J. 2022 May 2;41(9):e110466.
• LDL receptor-peptide conjugate as in vivo tool for specific targeting of pancreatic ductal adenocarcinoma. Acier A, Godard M, Gassiot F, Finetti P, Rubis M, Nowak J, Bertucci F, Iovanna JL, Tomasini R, Lécorché P, Jacquot G, Khrestchatisky M, Temsamani J, Malicet C, Vasseur S, Guillaumond F. Commun Biol. 2021 Aug 19;4(1):987.
• The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer. Hussain Z, Nigri J, Tomasini R. Cancers (Basel). 2021 Jun 18;13(12):3040.
• Fountain of youth of pancreatic cancer cells: the extracellular matrix. Gouirand V, Vasseur S. Cell Death Discov. 2018 Jan 10;4:1.
• LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker. Bressy C, Lac S, Nigri J, Leca J, Roques J, Lavaut MN, Secq V, Guillaumond F, Bui TT, Pietrasz D, Granjeaud S, Bachet JB, Ouaissi M, Iovanna J, Vasseur S, Tomasini R. Cancer Res. 2018 Feb 15;78(4):909-921.
• Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Olivares O, Mayers JR, Gouirand V, Torrence ME, Gicquel T, Borge L, Lac S, Roques J, Lavaut MN, Berthezène P, Rubis M, Secq V, Garcia S, Moutardier V, Lombardo D, Iovanna JL, Tomasini R, Guillaumond F, Vander Heiden MG, Vasseur S. Nat Commun. 2017 Jul 7;8:16031.