High‐throughput proteomics of breast cancer interstitial fluid: identification of tumor subtype‐specific serologically relevant biomarkers

Terkelsen, Thilde; Pernemalm, Maria; Gromov, Pavel; Børresen‐Dale, Anna‐Lise; Krogh, Anders; Haakensen, Vilde Drageset; Lethiö, Janne; Papaleo, Elena; Gromova, Irina

doi:10.1002/1878-0261.12850

Cited by 22 publications

(24 citation statements)

References 150 publications

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“…Thus, metabolite amounts in naïve mice tissues do not correspond to the bioavailable amounts for leukemic cells. Techniques for interstitial uid isolation are emerging and could be greatly useful for better understanding of dialogues between microenvironment and leukemic cells 13,47 . A study of leukemic and microenvironmental sorted cells from these tissues could lead to further rewiring and dialogues observations that could be exploited for therapy.…”

Section: Discussionmentioning

confidence: 99%

In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

Cognet

Stuani

Farge

et al. 2021

Preprint

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Background Metabolic adaptation is a hallmark of cancer including acute myeloid leukemia (AML). Tumor microenvironment is also described as an essential support of leukemic metabolism. We explored how systemic and tissue metabolism was rewired in leukemia-bearing mice and upon chemotherapy. Methods Using AML cell line- and primary patient-derived xenograft models, we developed in vivo metabolomics to uncover the metabolic pattern of 10 tissues including plasma, bone marrow, spleen, liver, adipose tissue, lung, pancreas, kidney, heart and muscle. Results In vivo targeted mass spectrometry allowed metabolic characterization of tissues from naïve and AML-xenografted immunocompromised mice. AML xenotransplantation and cytarabine treatment induced AML cell type-dependent global changes in tissue metabolomes. Infiltration of high OxPHOS MOLM14 cells that are intrinsically chemoresistant, induced minor changes in tissue metabolomes. In contrast, low OxPHOS U937 xenograft led to major reprogramming of metabolic tissue niches for survival upon chemotherapy. Interestingly, plasma metabolite signatures could predict the oxidative phenotype of leukemic cells. Conclusion Major metabolic changes in host tissues play a crucial role in tumor xenotransplantation and define their OxPHOS state in AML. Since mitochondrial phenotype is an essential determinant of drug response in AML, plasma metabolite signatures might be novel biomarkers for patient stratification.

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Section: Discussionmentioning

confidence: 99%

In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

Cognet

Stuani

Farge

et al. 2021

Preprint

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“…Also, current studies suggest implication of both the a and b isoforms, making it an important consideration for drug development. Further, in a recent comprehensive analysis of the secretome of breast cancer, the tumor interstitial fluid (TIF) proteome was characterized and identified PI5P4Kb as one of the 10 proteins that can be used as a reliable biomarker to stratify the breast cancer tumor subtypes, all of which were also analyzed by immunohistochemistry (IHC) on matched tumor tissue samples [42]. In summary, all of the above data points to clinical relevance of PI5P4Ks in breast cancer and to a promising outcome with the targeting of PI5P4Ks in a broad population of breast cancer patients, particularly including those that harbor altered TP53 status.…”

Section: Breast Cancermentioning

confidence: 99%

Expanding role of PI5P4Ks in cancer: A promising druggable target

2021

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Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are a family of druggable stress-regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies. Further, PI5P4Ks have a synthetic lethal interaction with the tumor suppressor p53, the loss of which is one of the most prevalent genetic drivers of malignant transformation. PI5P4K's emergence as a crucial axis in the expanding landscape of phosphoinositide signaling in cancer has already stimulated the development of specific inhibitors. Thus, a better understanding of the biology of the PI5P4Ks will allow for targeted and effective therapeutic interventions. Here, we attempt to summarize the mounting roles of the PI5P4Ks in cancer, including evidence that targeting them is a therapeutic vulnerability and promising nextin-line treatment for multiple cancer subtypes.

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“…A recent study suggested that THTPA, among several other proteins, might serve as biomarkers for stratification of tumor subtypes in breast cancer [ 92 ].…”

Section: Thiamine Triphosphatasesmentioning

confidence: 99%

Update on Thiamine Triphosphorylated Derivatives and Metabolizing Enzymatic Complexes

Bettendorff

2021

Biomolecules

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While the cellular functions of the coenzyme thiamine (vitamin B1) diphosphate (ThDP) are well characterized, the triphosphorylated thiamine derivatives, thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), still represent an intriguing mystery. They are present, generally in small amounts, in nearly all organisms, bacteria, fungi, plants, and animals. The synthesis of ThTP seems to require ATP synthase by a mechanism similar to ATP synthesis. In E. coli, ThTP is synthesized during amino acid starvation, while in plants, its synthesis is dependent on photosynthetic processes. In E. coli, ThTP synthesis probably requires oxidation of pyruvate and may play a role at the interface between energy and amino acid metabolism. In animal cells, no mechanism of regulation is known. Cytosolic ThTP levels are controlled by a highly specific cytosolic thiamine triphosphatase (ThTPase), coded by thtpa, and belonging to the ubiquitous family of the triphosphate tunnel metalloenzymes (TTMs). While members of this protein family are found in nearly all living organisms, where they bind organic and inorganic triphosphates, ThTPase activity seems to be restricted to animals. In mammals, THTPA is ubiquitously expressed with probable post-transcriptional regulation. Much less is known about the recently discovered AThTP. In E. coli, AThTP is synthesized by a high molecular weight protein complex from ThDP and ATP or ADP in response to energy stress. A better understanding of these two thiamine derivatives will require the use of transgenic models.

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High‐throughput proteomics of breast cancer interstitial fluid: identification of tumor subtype‐specific serologically relevant biomarkers

Cited by 22 publications

References 150 publications

In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

Expanding role of PI5P4Ks in cancer: A promising druggable target

Update on Thiamine Triphosphorylated Derivatives and Metabolizing Enzymatic Complexes

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