bims-tumime 2023-11-05 papers

bims-tumime

Biomed News

on Tumor microenvironment and metabolism

Issue of 2023‒11‒05
seven papers selected by
Alex Muir, University of Chicago

Metabolic pathway analysis using stable isotopes in patients with cancer.
Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
FAAH inhibition ameliorates breast cancer in a murine model.
Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation.
Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.
PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Nat Rev Cancer. 2023 Oct 31.

Metabolic pathway analysis using stable isotopes in patients with cancer.

Caroline R Bartman, Brandon Faubert, Joshua D Rabinowitz, Ralph J DeBerardinis.

Metabolic reprogramming is central to malignant transformation and cancer cell growth. How tumours use nutrients and the relative rates of reprogrammed pathways are areas of intense investigation. Tumour metabolism is determined by a complex and incompletely defined combination of factors intrinsic and extrinsic to cancer cells. This complexity increases the value of assessing cancer metabolism in disease-relevant microenvironments, including in patients with cancer. Stable-isotope tracing is an informative, versatile method for probing tumour metabolism in vivo. It has been used extensively in preclinical models of cancer and, with increasing frequency, in patients with cancer. In this Review, we describe approaches for using in vivo isotope tracing to define fuel preferences and pathway engagement in tumours, along with some of the principles that have emerged from this work. Stable-isotope infusions reported so far have revealed that in humans, tumours use a diverse set of nutrients to supply central metabolic pathways, including the tricarboxylic acid cycle and amino acid synthesis. Emerging data suggest that some activities detected by stable-isotope tracing correlate with poor clinical outcomes and may drive cancer progression. We also discuss current challenges in isotope tracing, including comparisons of in vivo and in vitro models, and opportunities for future discovery in tumour metabolism.

DOI: https://doi.org/10.1038/s41568-023-00632-z
bioRxiv. 2023 Oct 19. pii: 2023.10.16.562128. [Epub ahead of print]

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.

C Galvan, A Flores, V Cerrillos, I Avila, C Murphy, W Zheng, T T To, H R Christofk, W E Lowry.

Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent[1, 2]. However, despite the knowledge that nearly every cancer is associated with the strong upregulation of various metabolic pathways, there has yet to be much clinical progress on the treatment of cancer by targeting a single metabolic enzyme directly[3-6]. We previously showed that inhibition of glycolysis through lactate dehydrogenase (LDHA) deletion in cancer cells of origin had no effect on the initiation or progression of cutaneous squamous cell carcinoma[7], suggesting that these cancers are metabolically flexible enough to produce the necessary metabolites required for sustained growth in the absence of glycolysis. Here we focused on glutaminolysis, another metabolic pathway frequently implicated as important for tumorigenesis in correlative studies. We genetically blocked glutaminolysis through glutaminase (GLS) deletion in cancer cells of origin, and found that this had little effect on tumorigenesis, similar to what we previously showed for blocking glycolysis. Tumors with genetic deletion of glutaminolysis instead upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We also found that the metabolic flexibility observed upon inhibition of glycolysis or glutaminolysis is due to post-transcriptional changes in the levels of plasma membrane lactate and glutamine transporters. To define the limits of metabolic flexibility in cancer initiating hair follicle stem cells, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that frank carcinoma was not compatible with abrogation of both of these carbon utilization pathways. These data point towards metabolic flexibility mediated by regulation of nutrient consumption, and suggest that treatment of cancer through metabolic manipulation will require multiple interventions on distinct pathways.

DOI: https://doi.org/10.1101/2023.10.16.562128
Oncotarget. 2023 Oct 31. 14 910-918

FAAH inhibition ameliorates breast cancer in a murine model.

Mallika Tripathy, Amy Bui, Jared Henderson, Jeffrey Sun, Christian Rutan Woods, Soumya Somani, Thao Doan, Anto Sam Crosslee Louis Sam Titus, Chandra Mohan.

  Breast cancer is the leading cancer among females worldwide. Disease outcome depends on the hormonal status of the cancer and whether or not it is metastatic, but there is a need for more efficacious therapeutic strategies where first line treatment fails. In this study, Fatty Acid Amide Hydrolase (FAAH) inhibition and endocannabinoids were examined as therapeutic alternatives. FAAH is an integral membrane enzyme that hydrolyzes endocannabinoids, rendering them inactive, and FAAH inhibition is predicted to increase cancer cell death. To test this, breast cancer cells were probed for FAAH expression using Western blot analysis, treated with FAAH inhibitors, exogenous endocannabinoids, and combinations of the two treatments, and assessed for viability. High levels of FAAH were observed in different breast cancer cell lines. FAAH inhibition was more effective than exogenous endocannabinoid treatment, and the combination of FAAH inhibitors and endocannabinoids was the most effective in inducing apoptosis of breast cancer cells in vitro. In addition, in vivo FAAH inhibition reduced breast cancer growth in immunodeficient mice. FAAH inhibition is a promising approach, and tremendous progress has been made in the field to validate this mechanism as an alternative to chemotherapy. Further research exploring the therapeutic potential and impact of FAAH expression on cancer cells is warranted.

Keywords:  FAAH; apoptosis; breast cancer; cancer therapy

DOI:  https://doi.org/10.18632/oncotarget.28534
Cell Metab. 2023 Oct 26. pii: S1550-4131(23)00372-8. [Epub ahead of print]

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation.

Anni M Y Zhang, Yi Han Xia, Jeffrey S H Lin, Ken H Chu, Wei Chuan K Wang, Titine J J Ruiter, Jenny C C Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning Howard Cen, Elizabeth J Rideout, Vincent R Richard, David F Schaeffer, Rene P Zahedi, Christoph H Borchers, James D Johnson, Janel L Kopp.

  The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

Keywords:  Kras; PanIN; acinar cells; hyperinsulinemia; inflammation; insulin receptor; insulin resistance; obesity; pancreatic cancer; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.cmet.2023.10.003
bioRxiv. 2023 Oct 20. pii: 2023.10.17.562670. [Epub ahead of print]

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.

Zuzanna Nowicka, Frederika Rentzeperis, Richard Beck, Vural Tagal, Ana Forero Pinto, Elisa Scanu, Thomas Veith, Jackson Cole, Didem Ilter, William Dominguez Viqueira, Jamie K Teer, Konstantin Maksin, Stefano Pasetto, Mahmoud A Abdalah, Giada Fiandaca, Sandhya Prabhakaran, Andrew Schultz, Maureiq Ojwang, Jill S Barnholtz-Sloan, Joaquim M Farinhas, Ana P Gomes, Parag Katira, Noemi Andor.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumor's cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

DOI: https://doi.org/10.1101/2023.10.17.562670
Nat Metab. 2023 Oct 30.

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.

Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun.

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.

DOI: https://doi.org/10.1038/s42255-023-00912-w
bioRxiv. 2023 Oct 16. pii: 2023.10.12.562134. [Epub ahead of print]

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Chad VanSant-Webb, Hayden K Low, Junko Kuramoto, Claire E Stanley, Hantao Qiang, Audrey Su, Alexis N Ross, Chad G Cooper, James E Cox, Scott A Summers, Kimberley J Evason, Gregory S Ducker.

Background and Aims: Activating mutations in the CTNNB1 gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). HCC with CTNNB1 mutations show profound alterations in lipid metabolism including increases in fatty acid oxidation and transformation of the phospholipidome, but it is unclear how these changes arise and whether they contribute to the oncogenic program in HCC.Methods: We employed untargeted lipidomics and targeted isotope tracing to quantify phospholipid production fluxes in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC.
Results: In both models, activated β-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid flux analysis in human cells revealed a large reduction in phosphatidylcholine (PC) production rates as assayed by choline tracer incorporation. We developed isotope tracing lipid flux analysis for zebrafish and observed similar reductions in phosphatidylcholine synthesis flux accomplished by sex-specific mechanisms.
Conclusions: The integration of isotope tracing with lipid abundances highlights specific lipid class transformations downstream of β-catenin signaling in HCC and suggests future HCC-specific lipid metabolic targets.
Synopsis: In this work, we show by lipid specific isotope tracing that mutations in the oncogene CTNNB1 leads to conserved changes in lipid metabolism in hepatocellular carcinoma. These include the stimulation of fatty acid oxidation and a suppression of phosphorylcholine synthesis.

DOI: https://doi.org/10.1101/2023.10.12.562134