Metabolic dialogue between pancreatic cancer and gut microbiota

Offre de thèse

Équipe Immunité & Cancer du CRCM
Superviseur au CRCM : Dr. Alice CARRIER, alice.carrier@inserm.fr
Co-superviseur au BIP-IMM : Dr. Magali ROGER, mroger@imm.cnrs.fr

Annonce en anglais

Project title

Metabolic dialogue between pancreatic cancer and gut microbiota

Project description

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer. It is a lethal, late-diagnosing cancer that is resistant to current therapies, including immunotherapy (IT). A major mechanism behind PDAC resistance is the presence of an abundant immunosuppressive tumor microenvironment abolishing the activity of anti-tumor immune cells. PDAC is also characterized by a metabolic reprogramming of tumor cells, and also of immune cells and the body host's metabolic organs at distance. In addition, PDAC induces very debilitating cachexia in patients, with metabolic organs such as skeletal muscles melting away, making patients very weak.

It has recently been recognized that pancreatic tumors contain microbes that can influence their therapeutic response (1, 2). Intratumoral microbiota also impacts the immune profile of pancreatic tumors (3). Beyond that, it's the distant gut microbiota that can influence the therapeutic response of PDAC, in particular via a metabolite produced by the gut microbiota (4). Surprisingly, while numerous studies suggest the importance of the metabolic dialogue between tumor and microbiota on response and resistance to IT, little is known about the putative regulation of gut microbiota metabolism by treatments targeting tumor metabolism, and by patients' nutritional and metabolic status.

In this proposal, our aim is to test this hypothesis in a preclinical context, using a holistic approach combining the expertise of two research groups, the first specializing in PDAC and the second in microbial ecology and metabolism. The objective of the PhD project is to evaluate the impact of chemotherapy and drugs targeting energy metabolism, as well as that of physical activity able to control cachexia, on immunometabolism and response to IT. This will be achieved through an integrative study at tissue, cellular and molecular levels. Pancreas of mice developing PDAC will be analyzed by cutting-edge single cell technologies: spectral flow cytometry, spatial proteomics and CITE-sequencing (scRNA-seq coupled with proteomics). Microbial metabolites will be analyzed in the plasma of the same mice, in comparison with healthy mice, and subjected or not to various treatments. Blood plasma will be analyzed by HPLC and NMR to quantify secreted metabolites of microbial origin. Fecal microbiota will also be genotyped. The link with bacterial metabolism and the ecology of the gut microbiota will be established.

Alice Carrier’s laboratory has been working for several years to identify metabolic vulnerabilities that can be targeted clinically. For example, we have highlighted the possibility of inhibiting mitochondrial metabolism (the main source of cellular energy) to improve tumor response to chemotherapy (5, 6). We are now focusing on immunometabolism in the micro- and macro-environment, since metabolic reprogramming is able to orientate the function and fate of anti-tumoral immune cells. In addition, we are interested in the metabolic dialogue of the pancreatic tumor with the digestive tract and the microbiota it contains.

Magali Roger is a molecular microbiologist who has been working for several years on microbial metabolism at multiscale levels, from the characterization of microbial enzymes to complex metabolic network in microbial communities (7-9). In continuity, her current research focuses on developing synthetic microbial consortia to decipher the molecular basis of metabolic cooperation between microbes in complex ecosystems.

We expect this innovative project to reveal markers of the dialogue between the digestive tract and the pancreatic tumor, via the gut microbiota and the immune system. Understanding how the tumor modulates microbiota behaviors will pave the way towards enhancement of cancer treatments. Finally, the interdisciplinary nature of the project will also allow us to train a graduate student in broader approaches.

References:

1.   McAllister F, Khan MAW, Helmink B, Wargo JA. The Tumor Microbiome in Pancreatic Cancer: Bacteria and Beyond. Cancer Cell. 2019;36(6):577-9.

2.   Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell. 2019;178(4):795-806 e12.

3.   Ghaddar B, Biswas A, Harris C, Omary MB, Carpizo DR, Blaser MJ, et al. Tumor microbiome links cellular programs and immunity in pancreatic cancer. Cancer Cell. 2022;40(10):1240-53 e5.

4.   Tintelnot J, Xu Y, Lesker TR, Schonlein M, Konczalla L, Giannou AD, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023;615(7950):168-74.

5.   Reyes-Castellanos G, Abdel Hadi N, Gallardo-Arriaga S, Masoud R, Garcia J, Lac S, et al. Combining the antianginal drug perhexiline with chemotherapy induces complete pancreatic cancer regression in vivo. iScience. 2023;26(6):106899.

6.   Masoud R, Reyes-Castellanos G, Lac S, Garcia J, Dou S, Shintu L, et al. Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer. Cell Rep Med. 2020;1(8):100143.

7.   Roger M, Leone P, Blackburn NJ, Horrell S, Chicano TM, Biaso F, et al. Beyond the coupled distortion model: structural analysis of the single domain cupredoxin AcoP, a green mononuclear copper centre with original features. Dalton Trans. 2024;53(4):1794-808.

8.   Roger M, Reed TCP, Sargent F. Harnessing Escherichia coli for Bio-Based Production of Formate under Pressurized H(2) and CO(2) Gases. Appl Environ Microbiol. 2021;87(21):e0029921.

9.   Marbehan X, Roger M, Fournier F, Infossi P, Guedon E, Delecourt L, et al. Combining metabolic flux analysis with proteomics to shed light on the metabolic flexibility: the case of Desulfovibrio vulgaris Hildenborough. Front Microbiol. 2024;15:1336360.