Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Marusyk, Andriy; Janiszewska, Michalina; Polyák, Kornélia

doi:10.1016/j.ccell.2020.03.007

Cited by 532 publications

(373 citation statements)

References 159 publications

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“…Furthermore, the invasion front is known to be a hypoxic area in CRCs (Righi et al, 2015). Since the mechanism identified in this study relied on quantitative expression of DPD by macrophages, the assessment of the spatial heterogeneity of DPD expression will be necessary to stratify patients in various response groups for chemotherapy (Marusyk et al, 2020). Thus this study constitutes an important advance in the understanding of the role of tumor immune environment in chemoresistance to 5-FU in CRC.…”

Section: Discussionmentioning

confidence: 96%

Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Malier

Court

Gharzeddine

et al. 2020

Preprint

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Colon adenocarcinoma is characterized by an infiltration of tumor-associated macrophages (TAMs). TAMs are associated with a chemoresistance to 5-Fluorouracil (5-FU), but the mechanisms involved are still poorly understood. In the present study, we found that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to a macrophage-induced chemoresistance to 5-FU by inactivation of the drug. Macrophage DPD expression in hypoxia is translationally controlled by the cap-dependent protein synthesis complex eIF4FHypoxic, which includes HIF-2α. We discovered that TAMs constitute the main contributors to DPD activity in human colorectal primary or secondary tumors where cancer cells do not express significant levels of DPD. Together, these findings shed light on the role of TAMs in forming chemoresistance in colorectal cancers and offer the identification of new therapeutic targets. Additionally, we report that, contrary to what is found in humans, macrophages in mice do not express DPD.

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Section: Discussionmentioning

confidence: 96%

Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Malier

Court

Gharzeddine

et al. 2020

Preprint

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“…This might involve changes in the ECM as evidenced by the altered expression of 28 transcripts encoding several of its components, including enzymes such as matrix metallo-proteases or several cell-cell or cell-matrix adhesion molecules. Such changes often affect chemotherapeutic sensitivity and could impact the efficiency with which DDDA traverses the vasculature and enters tumor cells (64)(65)(66)(67)(68)(69). The down-regulation of transcripts encoding endothelial cell-related proteins such as Eng, Angptl7, Esam and Scarf2 might further contribute to alterations in blood vessel permeability.…”

Section: Discussionmentioning

confidence: 99%

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Wang

Chen

Schwalbe

et al. 2020

Preprint

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Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial β- and peroxisomal ω-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

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“…Several excellent reviews have recently described the current mechanisms of resistance in cancers [2][3][4][5][6][7][8] . Figure 1 provides an overview of the main mechanisms responsible for the acquisition of resistance to drugs by tumors.…”

Section: Most Common Cellular Mechanismsmentioning

confidence: 99%

Drug resistance in glioblastoma: are persisters the key to therapy?

Oliver¹,

Lalier²,

Salaud³

et al. 2020

CDR

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Glioblastoma (GBM) represents the main form of brain tumors in adults, and one of the most aggressive cancers overall. The treatment of GBM is a combination of surgery (when possible), chemotherapy (usually Temozolomide, TMZ) and radiotherapy (RT). However, despite this heavy treatment, GBM invariably recur and the median length of survival following diagnosis is 12 to 15 months, with less than 10% of people surviving longer than five years. GBM is extremely resistant to most treatments because of its heterogeneous nature, which is associated with extreme clonal plasticity and the presence of cancer stem cells, refractory to TMZ-and RT-induced cell death. In this review, we explore the mechanisms by which cancer cells, and especially GBM, can acquire resistance to treatment. We describe and discuss the concept of persister/tolerant cells that precede and/or accompany the acquisition of resistance. Persister/tolerant cells are cancer cells that are not eliminated by treatment(s) because of different mechanisms ranging from dormancy/quiescence to senescence. We discuss the possibility of targeting these mechanisms in new therapeutic regimen.

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Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Cited by 532 publications

References 159 publications

Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Drug resistance in glioblastoma: are persisters the key to therapy?

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