bims-tumime 2024-04-07 papers

Issue of 2024–04–07
five papers selected by
Alex Muir, University of Chicago

Cancer Discov. 2024 Apr 04. 14(4): 653-657

Tumor-Host Cometabolism Collaborates to Shape Cancer Immunity.

Yingcheng Wu, Qiang Zou, Peng Jiang, Qiang Gao.

SUMMARY: Nutrients are essential for supporting tumor growth and immune cell function in the tumor microenvironment, but emerging evidence reveals a paradoxical competition and collaboration between the metabolic demands of proliferating cancer cells and immune cell activation. Dietary interventions and metabolic immunoengineering offer promise to selectively modulate cancer and immune cell metabolism by targeting metabolic sensing processes rather than pathways directly, moving beyond conventional ideas and heralding an exciting new era of immunometabolism discovery and translation.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1509

Mol Metab. 2024 Apr 01. pii: S2212-8778(24)00061-9. [Epub ahead of print] 101930

Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis.

Camille Lefevre, Morgane M Thibaut, Audrey Loumaye, Jean-Paul Thissen, Audrey M Neyrinck, Benoit Navez, Nathalie M Delzenne, Olivier Feron, Laure B Bindels.

OBJECTIVE: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia.
METHODS: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes.
RESULTS: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocyte and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for β-glucuronidase as a promising new actor in adipocyte lipolysis.
CONCLUSIONS: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for dual therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.

Keywords: Adipocytes; Adipose tissue; Beta-glucuronidase; Cancer cachexia; Lipolysis; Tumor acidosis

DOI: https://doi.org/10.1016/j.molmet.2024.101930

Trends Cancer. 2024 Apr 04. pii: S2405-8033(24)00053-0. [Epub ahead of print]

Exploiting the metabolic vulnerability of circulating tumour cells.

Munise Merteroglu, Massimo M Santoro.

Metastasis has a major part in the severity of disease and lethality of cancer. Circulating tumour cells (CTCs) represent a reservoir of metastatic precursors in circulation, most of which cannot survive due to hostile conditions in the bloodstream. Surviving cells colonise a secondary site based on a combination of physical, metabolic, and oxidative stress protection states required for that environment. Recent advances in CTC isolation methods and high-resolution 'omics technologies are revealing specific metabolic pathways that support this selection of CTCs. In this review, we discuss recent advances in our understanding of CTC biology and discoveries of adaptations in metabolic pathways during their selection. Understanding these traits and delineating mechanisms by which they confer acquired resistance or vulnerability in CTCs is crucial for developing successful prognostic and therapeutic strategies in cancer.

Keywords: cancer; circulating tumour cells (CTCs); ferroptosis; metabolism; metastasis; oxidative stress

DOI: https://doi.org/10.1016/j.trecan.2024.03.004

Cancer Cell. 2024 Mar 31. pii: S1535-6108(24)00090-4. [Epub ahead of print]

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

Ningning Niu, Xuqing Shen, Zheng Wang, Yueyue Chen, Yawen Weng, Feier Yu, Yingying Tang, Ping Lu, Mingzhu Liu, Liwei Wang, Yongwei Sun, Minwei Yang, Baiyong Shen, Jiabin Jin, Zipeng Lu, Kuirong Jiang, Yufeng Shi, Jing Xue.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Keywords: OXPHOS; Pancreatic cancer; SETD2; cell communication; epigenetic dysregulation; lipid-laden CAF

DOI: https://doi.org/10.1016/j.ccell.2024.03.005

Anim Cells Syst (Seoul). 2024 ;28(1): 123-136

Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.

Seung Woo Kim, Chan Woo Kim, Young-Ah Moon, Hong Seok Kim.

The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.

Keywords: Cancer; TAM; metabolites; polarization; tumor microenvironment

DOI: https://doi.org/10.1080/19768354.2024.2336249