bims-tumime 2024-04-14 papers

Issue of 2024–04–14
five papers selected by
Alex Muir, University of Chicago

Cancer Discov. 2024 Mar 29. OF1-OF19

Metabolic Signaling in Cancer Metastasis.

Sarah Krieg, Sara Isabel Fernandes, Constantinos Kolliopoulos, Ming Liu, Sarah-Maria Fendt.

Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein-protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis.
SIGNIFICANCE: Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0174

Int J Mol Sci. 2024 Mar 25. pii: 3642. [Epub ahead of print]25(7):

Tumor Microenvironment: Cellular Interaction and Metabolic Adaptations.

Monica Benvenuto, Chiara Focaccetti.

The tumor microenvironment (TME) plays a critical role in cancerogenesis [...].

DOI: https://doi.org/10.3390/ijms25073642

Nat Cell Biol. 2024 Apr 11.

A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.

Christopher Chidley, Alicia M Darnell, Benjamin L Gaudio, Evan C Lien, Anna M Barbeau, Matthew G Vander Heiden, Peter K Sorger.

Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.

DOI: https://doi.org/10.1038/s41556-024-01402-1

J Physiol Biochem. 2024 Apr 08.

Fasting and fasting-mimicking conditions in the cancer immunotherapy era.

Ruben Pio, Yaiza Senent, Beatriz Tavira, Daniel Ajona.

Fasting and fasting-mimicking conditions modulate tumor metabolism and remodel the tumor microenvironment (TME), which could be exploited for the treatment of tumors. A body of evidence demonstrates that fasting and fasting-mimicking conditions can kill cancer cells, or sensitize them to the antitumor activity of standard-of-care drugs while protecting normal cells against their toxic side effects. Pre- and clinical data also suggest that immune responses are involved in these therapeutic effects. Therefore, there is increasing interest in evaluating the impact of fasting-like conditions in the efficacy of antitumor therapies based on the restoration or activation of antitumor immune responses. Here, we review the recent progress in the intersection of fasting-like conditions and current cancer treatments, with an emphasis on cancer immunotherapy.

Keywords: Cancer immunotherapy; Cancer treatment toxic side effects; Fasting; Fasting-mimicking conditions; Tumor immunity

DOI: https://doi.org/10.1007/s13105-024-01020-3

Cell. 2024 Apr 08. pii: S0092-8674(24)00255-1. [Epub ahead of print]

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Keywords: DNA repair and replication; breast cancer gene BRCA2; cancer genome; cancer metabolism; environmental carcinogenesis; gene-environment interaction; glycolysis; methylglyoxal; mutational signature; tumor suppression

DOI: https://doi.org/10.1016/j.cell.2024.03.006