The Dutch Cancer Society (KWF Kankerbestrijding) has awarded a total of € 2,7 million to four Amsterdam UMC research groups to unravel fundamental biological features of cancer as a basis for developing new treatments. One of the awarded project proposals is entitled: “‘Bugging chemoresistance’: bench-to-bedside studies to unravel and target the mechanisms underlying bacteria-induced chemoresistance in pancreatic cancer” (€ 624.775,90).
Led by principal investigator Elisa Giovannetti and collaborators Dongmei Deng, Geert Kazemier, and Reina Mebius, this multidisciplinary team aims to elucidate the role of intra-tumoral microbiome in mediating chemoresistance observed in pancreatic cancer. By understanding this interaction, the researchers aim to find ways to interfere with bacteria-induced chemoresistance and develop new therapeutic and clinical management strategies for patients.
Pancreatic cancer has limited treatment options due to the drug-resistant nature of this tumor. This hallmark chemoresistance is attributed to its genetic instability, metabolic abnormalities, and the complex tumor microenvironment. A better understanding of resistance mechanisms is essential for improving the prognosis of patients
Recently, an increasing number of tumors have been reported to harbor bacteria, with different tumor types having a distinct set of bacteria. In addition, recent evidence suggests that this tumor microbiome may be a potential driver of anticancer drug resistance. However, evidence is limited at this point, with most studies showing merely correlational associations, and lack insight into the causal relationships between host-cancer-microbiome and chemoresistance.
What is the role of bacteria in chemoresistance?
In this KWF-funded project, a team including researchers from Cancer Center Amsterdam (CCA), Amsterdam institute for Infection and Immunity (AII), and Academic Center for Dentistry (ACTA) will collaborate to investigate the hypothesis that that the tumor and its microbial composition have complementary molecular mechanisms underlying chemoresistance in pancreatic ductal adenocarcinoma (PDAC)..
“We know that the efficacy of some chemotherapeutics, including gemcitabine, is inhibited by several bacteria enriched in PDAC,” says Dr. Elisa Giovanetti. “In addition, recent studies showed that tumor bacteria modulate specific oncogenic pathways, including ones involved in metastasis or chemoresistance. So it makes sense that learning more about biological pathways bacteria are affecting in a tumor cells may potentially evolve into treatments to overcome cancer resistance.”
Investigating candidate bacteria
To establish causal connections, the collaborators will establish suitable model systems consisting of early-passaged primary PDAC cells which have similar genetic profiles to the original tumors and can be cultivated in 2D/3D co-cultures with the cells from the tumor microenvironment, allowing them to introduce candidate bacteria.
This project has important potential clinical implications. “The ultimate goal is indeed to improve pharmacological treatment and personalized clinical management of patients with pancreatic cancer in the near future,” says Dr. Giovannetti. “If bacterial within tumor cells are helping them resist chemotherapy, we can learn to disrupt this interaction and thus make existing therapies more effective. In addition, learning more about host-tumor-microbiome interactions opens the door to developing more effective therapies.”
For more information, contact Dr. Elisa Giovannetti, or read this scientific review:
Capula, M., et al. (2022) Role of drug catabolism, modulation of oncogenic signaling and tumor microenvironment in microbe-mediated pancreatic cancer chemoresistance. Drug Resistance Updates, 64,100864, https://doi.org/10.1016/j.drup.2022.100864.
Researchers involved:
Elisa Giovannetti, Dept. of Medical Oncology, Amsterdam UMC - Cancer Center Amsterdam
Geert Kazemier, Dept. of Surgery, Amsterdam UMC - Cancer Center Amsterdam
Dongmei Deng, Academisch Centrum Tandheelkunde Amsterdam (ACTA)
Reina Mebius, Molecular Cell Biology & Immunology (MCBI), Amsterdam UMC - Cancer Center Amsterdam and Amsterdam institute for Infection and Immunity
This research project is funded by Dutch Cancer Society (KWF Kankerbestrijding)
Text by Elisa Giovannetti
This article was created for Cancer Center Amsterdam.