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Many chemotherapies induce cell death in a subset of tumor cells, but there remains a question of whether this death enables survival of the remaining malignant cells. Using patient-derived colorectal cancer organoids treated with the chemotherapy 5-fluorouracil, Schmitt and colleagues found efficient induction of the mechanistic target of rapamycin (mTOR) pathway in surviving cancer cells, specifically, mTOR complex 1 and its indirect target p-S6. Coadministration of the mTOR inhibitor rapamycin and 5-fluorouracil led to synergistic inhibition of cancer cell survival in organoids and xenografts. Through systematic testing in a mouse model of colorectal cancer, the authors showed that mTOR signaling was driven by paracrine release of ATP from dying cells and required the P2X4 receptor. Inhibition of P2X4, like inhibition of mTOR, greatly decreased tumor graft size when combined with 5-floururacl.

Expert Commentary: This work identifies a potential combination therapy not easily predicted by genomic alterations and suggests that profiling of protein-level activity may highlight approaches to enhance tumor cell killing.

Schmitt M, Ceteci F, Gupta J, Pesic M, Böttger TW, Nicolas AM, et al. Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation. Nature 2022;612:347–53.

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Lung cancer, the leading cause of cancer-related deaths, has an abysmal 5-year survival rate. Lung cancers driven by KRAS mutations have limited to no viable treatment options. Li and colleagues identified elevated levels of the B-cell lymphoma 6 (BCL6) oncogene in a conditional knock-in mouse model of KRAS-driven lung cancer and human lung cancer cell lines. Using a small- molecule inhibitor library of KRAS effectors, the authors identified the MEK inhibitor selumetinib as the most effective in reducing BCL6 expression in the human cell lines H460 and H441. Mechanistically, selumetinib attenuated activity of the ETS transcription factor 1 (ELK1). ELK1 directly bound to the promoter of BCL6 and increased its gene expression. Genetic ablation of BCL6 impaired lung cancer development in their transgenic model, and a BCL6 inhibitor (COMP7) increased survival of KRAS-mutant lung tumor growth in vivo.

Expert Commentary: The proto-oncogene BCL6 has potential as druggable vulnerability in KRAS-driven lung cancer, which is lacking therapeutic interventions.

Li K, Liu Y, Ding Y, Zhang Z, Feng J, Hu J, et al. BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer. J Clin Invest 2022;132:e161308. doi: 10.1172/JCI161308.

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Acute myeloid leukemia (AML) shows distinct genetic profiles in pediatric and adult patients. The FLT3 internal tandem duplication (FLT3ITD) mutation occurs with similar incidence in children and adults, but co-occurring mutations vary. Li and colleagues set out to compare Flt3ITD AML in the setting of additional pediatric-based mutations in NUP98-HOXD13 (NHD13) as compared with an adult-biased RUNX1 loss-of-function mutation. A distinct leukemic-initiating profile was seen specifically in a hemopoietic progenitor population, the multipotent progenitor. FLT3ITD activated vastly different target genes and different target enhancers when paired with NHD13 as compared with RUNX1 mutations. Distinct to the pediatric FLT3ITD/NHD13 mutant leukemia was an interferon-1 responsive profile, shown to be therapeutically actionable. This work provides a biological understanding of the pediatric and adult AML co-mutational profile and of therapeutic strategies for children and adults with AML.

Expert Commentary: The findings show that FLT3ITD co-opts different mechanisms of transformation when it pairs with a pediatric-biased NUP98 fusion as compared to adult-biased mutations.

Li W, Yang W, Patel RM, Casey EB, Denby ED, Mendoza-Castrejon J, et al. FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation. Blood; Published online November 17, 2022; doi: 10.1182/blood.2022016889.

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Neutrophils often make up a large component of the tumor microenvironment, but their role is complex, as their presence has been associated with promoting or inhibiting specific types of cancer. Xue and colleagues examined human hepatocellular carcinomas by single-cell RNA-seq and defined 5 types of liver cancers based on the infiltrating immune components. Interestingly, an immune suppressive myeloid phenotype, dominated by neutrophils and macrophages, was most strongly associated with reduced progression-free survival. Tumor-associated neutrophils with high expression of the chemokine CCL4 and inhibitory ligand PD-L1 could be found in human and mouse liver cancers and were induced by culturing with human liver cancer cell supernatants. Blockade of PD-L1 binding to PD-1 on T cells restored T-cell activity in vitro and depletion of neutrophils in mouse models of liver cancer enhanced tumor control.

Expert Commentary: Tumor-associated neutrophils are immunosuppressive in liver cancer and their depletion enhances tumor control.

Xue R, Zhang Q, Cao Q, Kong R, Xiang X, Liu H, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 2022;612:141–7.

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Integrating transcriptomic and metabolomic analyses of subgroup-specific glioblastoma stem cells, Pieri and colleagues identified increased abundance of L-fucose in mesenchymal-specific glioblastoma stem cells, in their corresponding xenografts, and in human mesenchymal glioblastoma specimens. Genetic inhibition of FUT8 [α-(1,6)-fucosyltransferase], which specifically mediates core fucosylation, decreased growth of orthotopic mesenchymal glioblastoma xenografts. Treatment with fucose-analogs encumbered mesenchymal-specific glioblastoma stem cells core fucosylation, blocked proliferation in vitro, and inhibited growth in vivo. Mass spectrometry–based analysis revealed that mesenchymal-restricted core fucosylated proteins mediated extracellular matrix interactions, cell adhesion, and integrin signaling. Using preclinical positron emission tomography, the authors observed accumulation of L-fucose in mesenchymal glioblastoma, suggesting this as a minimally invasive imaging biomarker.

Expert Commentary: Metabolic characterization of subgroup-specific glioblastoma stem cells identified the L-fucose pathway as a liability restricted to mesenchymal glioblastoma. Dysregulated accumulation of L-fucose with enhanced core fucosylation represent candidate diagnostic markers and druggable targets in mesenchymal glioblastoma.

Pieri V, Gallotti AL, Drago D, Cominelli M, Pagano I, Conti V. et al. Aberrant L-fucose accumulation and increased core fucosylation are metabolic liabilities in mesenchymal glioblastoma. Cancer Res 2022;83:195–218.

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Acetyl-CoA is essential for the TCA cycle, de novo fatty acid synthesis and acetylation of proteins, pathways that are frequently perturbed in cancer. Of note, fatty acid oxidation enzymes show reduced expression levels in hepatocellular carcinoma. In a mouse model and hepatocellular carcinoma patient samples, Park and colleagues observed reduced activity and low acetyl-CoA levels in all six acetyl-CoA synthetic pathways. Proteins in many metabolic pathways were consequently hypoacetylated, leading to increased proliferation, dedifferentiation, and tumorigenesis. The authors further identified transcription factors TEAD2 and E2A as repressors of acetyl-CoA expression. Knockdown of TEAD and E2A knockdown restored expression of acetyl-CoA and reduced tumorigenesis.

Expert Commentary: This study suggests regulation of acetyl-CoA synthesis as a promising strategy for cancer therapy.

Park S, Mossman D, Chen Q, Wang X, Dazert E, Colombi M, et al. Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis. Molecular Cell 2022;82:4246-61.e11.

Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.