TY - JOUR
T1 - Role of drug catabolism, modulation of oncogenic signaling and tumor microenvironment in microbe-mediated pancreatic cancer chemoresistance
AU - Capula, Mjriam
AU - Perán, Macarena
AU - Xu, Geng
AU - Donati, Valentina
AU - Yee, Dicky
AU - Gregori, Alessandro
AU - Assaraf, Yehuda G.
AU - Giovannetti, Elisa
AU - Deng, Dongmei
N1 - Funding Information: This work was supported by the Pancreatic Cancer Europe (PCE) Short-term Scientific Stay Award, the ACCION 1_PAIUJA 2019-2020 BIO349 grant from the University of Jaén, Cancer Center Amsterdam grants ( CCA grants 2016 and 2018 ), KWF Dutch Cancer Society (KWF grant# 11957 ), and Associazione Italiana per la Ricerca sul Cancro ( AIRC /IG-grant 24444 ). We would like to thank Dr. E. Jordanova, I. Carnevale and S. Coppola for their technical assistance with the figures. Publisher Copyright: © 2022 The Authors
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) has one of the highest incidence/death ratios among all neoplasms due to its late diagnosis and dominant chemoresistance. Most PDAC patients present with an advanced disease characterized by a multifactorial, inherent and acquired resistance to current anticancer treatments. This remarkable chemoresistance has been ascribed to several PDAC features including the genetic landscape, metabolic alterations, and a heterogeneous tumor microenvironment that is characterized by dense fibrosis, and a cellular contexture including functionally distinct subclasses of cancer-associated fibroblasts, immune suppressive cells, but also a number of bacteria, shaping a specific tumor microbiome microenvironment. Thus, recent studies prompted the emergence of a new research avenue, by describing the role of the microbiome in gemcitabine resistance, while next-generation-sequencing analyses identified a specific microbiome in different tumors, including PDAC. Functionally, the contribution of these microbes to PDAC chemoresistance is only beginning to be explored. Here we provide an overview of the studies demonstrating that bacteria have the capacity to metabolically transform and hence inactivate anticancer drugs, as exemplified by the inhibition of the efficacy of 10 out of 30 chemotherapeutics by Escherichia coli. Moreover, a number of bacteria modulate specific oncogenic pathways, such as Fusobacterium nucleatum, affecting autophagy and apoptosis induction by 5-fluorouracil and oxaliplatin. We hypothesize that improved understanding of how chemoresistance is driven by bacteria could enhance the efficacy of current treatments, and discuss the potential of microbiome modulation and targeted therapeutic approaches as well as the need for more reliable models and biomarkers to translate the findings of preclinical/translational research to the clinical setting, and ultimately overcome PDAC chemoresistance, hence improving clinical outcome.
AB - Pancreatic ductal adenocarcinoma (PDAC) has one of the highest incidence/death ratios among all neoplasms due to its late diagnosis and dominant chemoresistance. Most PDAC patients present with an advanced disease characterized by a multifactorial, inherent and acquired resistance to current anticancer treatments. This remarkable chemoresistance has been ascribed to several PDAC features including the genetic landscape, metabolic alterations, and a heterogeneous tumor microenvironment that is characterized by dense fibrosis, and a cellular contexture including functionally distinct subclasses of cancer-associated fibroblasts, immune suppressive cells, but also a number of bacteria, shaping a specific tumor microbiome microenvironment. Thus, recent studies prompted the emergence of a new research avenue, by describing the role of the microbiome in gemcitabine resistance, while next-generation-sequencing analyses identified a specific microbiome in different tumors, including PDAC. Functionally, the contribution of these microbes to PDAC chemoresistance is only beginning to be explored. Here we provide an overview of the studies demonstrating that bacteria have the capacity to metabolically transform and hence inactivate anticancer drugs, as exemplified by the inhibition of the efficacy of 10 out of 30 chemotherapeutics by Escherichia coli. Moreover, a number of bacteria modulate specific oncogenic pathways, such as Fusobacterium nucleatum, affecting autophagy and apoptosis induction by 5-fluorouracil and oxaliplatin. We hypothesize that improved understanding of how chemoresistance is driven by bacteria could enhance the efficacy of current treatments, and discuss the potential of microbiome modulation and targeted therapeutic approaches as well as the need for more reliable models and biomarkers to translate the findings of preclinical/translational research to the clinical setting, and ultimately overcome PDAC chemoresistance, hence improving clinical outcome.
KW - Chemoresistance
KW - Chemotherapy
KW - Drug metabolism
KW - Microbiome
KW - Oncogenic pathways
KW - Pancreatic cancer
KW - Tumor microenvironment
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U2 - https://doi.org/10.1016/j.drup.2022.100864
DO - https://doi.org/10.1016/j.drup.2022.100864
M3 - Article
C2 - 36115181
SN - 1368-7646
VL - 64
SP - 1
EP - 16
JO - Drug resistance updates
JF - Drug resistance updates
M1 - 100864
ER -