Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1

Grobben, Yvonne; Ouden, Judith E. den; Aguado, Cristina; Altena, Anne M. van; Kraneveld, Aletta D.; Zaman, Guido J.R.

doi:10.3390/cancers15030893

Cited by 6 publications

(8 citation statements)

References 65 publications

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“…To our knowledge, this is the first report of such relationships in OCCC tissues. Previously, it was shown that l‐tryptophan is a major substrate of both IDO1 and IL4I1, and high levels of its metabolites were associated with IL4I1 activity in ascites from HGSOC patients 33 . Compared with that in normal tissue, TDO2 expression was upregulated in ovarian cancer tissues 32 .…”

Section: Discussionmentioning

confidence: 96%

“…22 Furthermore, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 in ascites was associated with advanced disease stage, suggesting a role of IL4I1 in HGSOC progression. 33 To date, the function of Trp metabolism in OCCC remains unclear. Therefore, in the present study, we investigated the in situ expression of enzymes of Trp metabolism in OCCC, including IDO1, IDO2, TDO2 and IL4I1, using immunohistochemistry (IHC) analysis of tissue microarrays (TMAs).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, overexpression of IL4I1 was shown to activate AHR and promote tumour progression 22 . Furthermore, elevated metabolism of l‐phenylalanine and l‐tyrosine by IL4I1 in ascites was associated with advanced disease stage, suggesting a role of IL4I1 in HGSOC progression 33 …”

Section: Introductionmentioning

confidence: 99%

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Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Zhang,

Gao,

Wang

et al. 2023

Cancer Medicine

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AimAs the second most prevalent subtype of epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) is known for its chemoresistance to conventional platinum‐based therapy. In this work, we examined the tryptophan (Trp) metabolism enzymes' differential expression in patients with OCCC to assess the potential for personalised treatment.MethodsA total of 127 OCCC tissues were used to construct tissue microarrays, and immunohistochemistry (IHC) staining of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 was performed. The correlations between Trp enzyme expression and clinical characteristics were analysed.ResultsPositive IDO1, IDO2, TDO2 and IL4I1 staining was identified in 26.8%, 94.5%, 75.6% and 82.7% of OCCC respectively. IDO1‐positive samples were more common in the chemoresistant group than in the platinum‐sensitive group (46.7% vs. 19.8%). Moreover, positive expression of IDO1, TDO2 and IL4I1 was related to advanced stage, metastasis, bilateral tumours, endometriosis and tumour rupture (p < 0.05) respectively. Univariate analysis revealed a significant association between bilateral tumours, lymph node metastasis, advanced stage, distant metastasis and aberrant cytology with a poor prognosis for OCCC, while the absence of residual tumour was correlated with a favourable outcome (p < 0.05). However, only bilateral tumours and lymph node metastases were related to a poor prognosis after multivariate analysis.ConclusionThis is the first study to investigate the expression of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 in OCCC tissues. IDO2, TDO2 and IL4I1 were detected in the majority of OCCC. Clinical traits were correlated with IDO1, IDO2, TDO2 and IL4I1 expression. IDO1 may be used as a therapeutic target given the large percentage of chemoresistant cases with IDO1 expression. These results will aid the development of personalised therapies for OCCC.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Zhang,

Gao,

Wang

et al. 2023

Cancer Medicine

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“…65 Likewise, we found that such a functional link, particularly between claudin-4 and LAT1, strongly suggest that one key cellular process driving aggressiveness in ovarian cancer in the transport of amino acids through the plasma membrane. This is interestingly because formation of ascites in common in advanced stage of ovarian cancer and ascites play a fundamental role in immune regulation via amino acids and their transport [94][95][96] Remarkably, in vivo targeting of claudin-4 not only affected tumor progression but also such targeting, improved the efficacy of niraparib treatment for HGSC tumors. This effect was related to immune modulation of some tumor clones.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer

Villagomez,

Lang,

Webb

et al. 2024

Preprint

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Genome instability is key for tumor heterogeneity and derives from defects in cell division and DNA damage repair. Tumors show tolerance for this characteristic, but its accumulation is regulated somehow to avoid catastrophic chromosomal alterations and cell death. Claudin-4 is upregulated and closely associated with genome instability and worse patient outcome in ovarian cancer. This protein is commonly described as a junctional protein participating in processes such as cell proliferation and DNA repair. However, its biological association with genomic instability is still poorly-understood. Here, we used CRISPRi and a claudin mimic peptide (CMP) to modulate the cladudin-4 expression and its function, respectively in in-vitro (high-grade serous carcinoma cells) and in-vivo (patient-derived xenograft in a humanized-mice model) systems. We found that claudin-4 promotes a protective cellular-mechanism that links cell-cell junctions to genome integrity. Disruption of this axis leads to irregular cellular connections and cell cycle that results in chromosomal alterations, a phenomenon associated with a novel functional link between claudin-4 and SLC1A5/LAT1 in regulating autophagy. Consequently, claudin-4 disruption increased autophagy and associated with engulfment of cytoplasm-localized DNA. Furthermore, the claudin-4/SLC1A5/LAT1 biological axis correlates with decrease ovarian cancer patient survival and targeting claudin-4 in-vivo with CMP resulted in increased niraparib (PARPi) efficacy, correlating with increased tumoral infiltration of T CD8+ lymphocytes. Our results show that the upregulation of claudin-4 enables a mechanism that promotes tolerance to genomic instability and immune evasion in ovarian cancer; thus, suggesting the potential of claudin-4 as a translational target for enhancing ovarian cancer treatment.

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Claudin-4 Modulates Autophagy via SLC1A5/LAT1 as a Mechanism to Regulate Micronuclei

Villagomez,

Lang,

Rosario

et al. 2024

Cancer Research Communications

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Genome instability is a hallmark of cancer crucial for tumor heterogeneity and is often a result of defects in cell division and DNA damage repair. Tumors tolerate genomic instability, but the accumulation of genetic aberrations is regulated to avoid catastrophic chromosomal alterations and cell death. In ovarian cancer tumors, claudin-4 is frequently upregulated and closely associated with genome instability and worse patient outcomes. However, its biological association with regulating genomic instability is poorly understood. Here, we used CRISPR interference and a claudin mimic peptide to modulate the claudin-4 expression and its function in vitro and in vivo. We found that claudin-4 promotes a tolerance mechanism for genomic instability through micronuclei generation in tumor cells. Disruption of claudin-4 increased autophagy and was associated with the engulfment of cytoplasm-localized DNA. Mechanistically, we observed that claudin-4 establishes a biological axis with the amino acid transporters SLC1A5 and LAT1, which regulate autophagy upstream of mTOR. Furthermore, the claudin-4/SLC1A5/LAT1 axis was linked to the transport of amino acids across the plasma membrane as one of the potential cellular processes that significantly decreased survival in ovarian cancer patients. Together, our results show that the upregulation of claudin-4 contributes to increasing the threshold of tolerance for genomic instability in ovarian tumor cells by limiting its accumulation through autophagy. Significance: Autophagy regulation via claudin-4/SLC1A5/LAT1 has the potential to be a targetable mechanism to interfere with genomic instability in ovarian tumor cells.

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Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1

Cited by 6 publications

References 65 publications

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer

Claudin-4 Modulates Autophagy via SLC1A5/LAT1 as a Mechanism to Regulate Micronuclei

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