Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Kay, Emily; Paterson, Karla; Riera-Domingo, Carla; Sumpton, David; Däbritz, J. Henry M.; Tardito, Saverio; Boldrini, Claudia; Hernández-Fernaud, Juan R.; Athineos, Dimitris; Dhayade, Sandeep; Stepanova, E. V.; Gjerga, Enio; Neilson, Lisa J.; Lilla, Sérgio; Hedley, Ann; Koulouras, Grigorios; McGregor, Grace H.; Jamieson, Craig; Johnson, Radia Marie; Park, Morag; Kirschner, Kristina; Miller, Crispin; Kamphorst, Jurre J.; Loayza‐Puch, Fabricio; Sáez-Rodríguez, Julio; Mazzone, Massimiliano; Blyth, Karen; Zagnoni, Michele; Zanivan, Sara

doi:10.1038/s42255-022-00582-0

Cited by 54 publications

(42 citation statements)

References 67 publications

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“…Proline synthesis in CAFs then enables production and deposition of collagen, a major component of the extracellular matrix. Suppression of PYCR1 in CAFs inhibits collagen deposition, tumor growth and metastatic potential in breast cancer ( 3 ). Consistently, autophagy deficiency in CAFs impedes proline biosynthesis and collagen deposition ( 166 ).…”

Section: Amino Acidsmentioning

confidence: 99%

“…Within the TME, cancer cells interact with and alter metabolism of these tumor resident non-transformed stromal cell types on multiple levels. For example, cancer associated fibroblasts (CAFs) upregulate collagen synthesis for extracellular matrix deposition ( 2 , 3 ), tumor associated ECs stimulate glycolysis to support angiogenesis, and various types of the immune cells such as macrophages or T-cells are modulated by the TME towards immunosuppression. Vice versa, stromal cells may supply cancer cells with metabolites, and cancer cells can obtain nutrients externally from the blood stream ( 4 ), which is facilitated by EC-driven angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Effects of metabolic cancer therapy on tumor microenvironment

et al. 2022

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Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly – clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

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Section: Amino Acidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of metabolic cancer therapy on tumor microenvironment

et al. 2022

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“…Finally, CAF metabolism directly influences ECM composition: the production of massive amounts of collagens by activated fibroblasts requires increased proline synthesis from circulating glutamine, and this relies on increased expression of pyrroline-5-carboxylate reductase 1 (PYCR1) in CAFs, which is in turn epigenetically regulated by histone acetyl-transferase EP300 and by acetyl-CoA levels [ 94 ]. This was demonstrated in detail in breast cancer models, but PYCR1 and collagen upregulation co-occurs in many tumor types [ 94 ], suggesting that this mechanism might have a broader relevance. As collagen abundance and ECM stiffness drive therapeutic resistance, these findings might represent another way by which metabolic cues influence drug response.…”

Section: Background: Being Cafsmentioning

confidence: 99%

“…Finally, as reported above, Kay et al recently demonstrated that proline synthesis via PYCR1 is a crucial regulator of enhanced collagen production by CAFs. Targeting PYCR1 in CAFs reduced tumour collagen deposition in vitro and in vivo and was sufficient to reduce tumour growth and metastasis [ 94 ]. PYCR1 is a particularly promising metabolic vulnerability, as it is among the most overexpressed genes across tumor types [ 123 ].…”

Section: Background: Being Cafsmentioning

confidence: 99%

The importance of being CAFs (in cancer resistance to targeted therapies)

Rizzolio

Giordano

Corso

2022

J Exp Clin Cancer Res

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In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. However, the efficacy of these therapies is significantly limited by primary and acquired resistance, that relies not only on cell-autonomous mechanisms but also on tumor microenvironment cues. Cancer-associated fibroblasts (CAFs) are extremely plastic cells of the tumor microenvironment. They not only produce extracellular matrix components that build up the structure of tumor stroma, but they also release growth factors, chemokines, exosomes, and metabolites that affect all tumor properties, including response to drug treatment. The contribution of CAFs to tumor progression has been deeply investigated and reviewed in several works. However, their role in resistance to anticancer therapies, and in particular to molecular therapies, has been largely overlooked. This review specifically dissects the role of CAFs in driving resistance to targeted therapies and discusses novel CAF targeted therapeutic strategies to improve patient survival.

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“…extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a major driver of cancer aggressiveness. Kay et al confirmed PYCR1 upregulation in all CAF lines by western blot analysis, and by targeting PYCR1 in CAFs in a breast cancer cotransplantation model, the size and weight of tumors in the PYCR1-expressing group were reduced, and the surrounding fibrillar collagen was significantly reduced, compared with the control group, which showed that reducing the PYCR1 levels in CAFs reduced tumor collagen production, tumor growth, and metastatic spread in vivo and cancer cell proliferation in vitro(29).…”

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confidence: 92%

Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis

Bao

et al. 2022

Front. Oncol.

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BackgroundProline metabolism is closely related to the occurrence and development of cancer. Δ1-Pyrroline-5-carboxylate reductase (PYCR) is the last enzyme in proline biosynthesis. As one of the enzyme types, PYCR1 takes part in the whole process of the growth, invasion, and drug resistance of cancer cells. This study investigated PYCR1 expressions in cancers together with their relationship to clinical prognosis.MethodsA thorough database search was performed in PubMed, EMBASE, and Cochrane Library. RevMan5.3 software was used for the statistical analysis.ResultsEight articles were selected, and 728 cancer patients were enrolled. The cancer types include lung, stomach, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. The meta-analysis results showed that the expression of PYCR1 was higher in the clinical stage III–IV group than that in the clinical stage I–II group (OR = 1.67, 95%CI: 1.03–2.71), higher in the lymph node metastasis group than in the non-lymph node metastasis group (OR = 1.57, 95%CI: 1.06–2.33), and higher in the distant metastasis group than in the non-distant metastasis group (OR = 3.46, 95%CI: 1.64–7.29). However, there was no statistical difference in PYCR1 expression between different tumor sizes (OR = 1.50, 95%CI: 0.89–2.53) and degrees of differentiation (OR = 0.82, 95%CI: 0.54–1.24).ConclusionPYCR1 had a high expression in various cancers and was associated with cancer volume and metastasis. The higher the PYCR1 expression was, the poorer the cancer prognosis was. The molecular events and biological processes mediated by PYCR1 might be the underlying mechanisms of metastasis.

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Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Cited by 54 publications

References 67 publications

Effects of metabolic cancer therapy on tumor microenvironment

Effects of metabolic cancer therapy on tumor microenvironment

The importance of being CAFs (in cancer resistance to targeted therapies)

Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis

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