Would KRAS Inhibition Promote Metastasis in Pancreatic Cancer?
The dependence of pancreatic ductal adenocarcinoma (PDAC) cells on the proto-oncogene KRAS is not completely understood. Muzumdar and colleagues used CRISPR/Cas technology to completely knockout (KO) KRAS in PDAC cell lines and found multiple lines gave rise to surviving KRAS KO clones that were able to form subcutaneous tumors in immunocompromised mice. Thus, KRAS was dispensable for proliferation of PDAC cells, even in vivo. The surviving KRAS KO cells displayed RTK-induced hyperactivation of PI3K and accordingly were sensitive to PI3K-inhibition, particularly using inhibitors that simultaneously inhibited PI3K and ERK. PI3K-inhibition synergized with acute deletion of KRAS in vivo, suggesting combinatorial therapy as a therapeutic strategy. Comparing KRAS retaining and KO cell lines revealed KRAS repressed genes enriched in circulating PDAC cells, linked to epithelial–mesenchymal transition and metastasis. Importantly, a 16-gene signature, suppressed by KRAS, independently correlated with survival in two patient cohorts. These data highlight the possibility of resistance to KRAS inhibitors and an alarming potential upregulation of metastasis-promoting genes upon KRAS blockade.
MCT1 Inhibition Enhances Mitochondrial Metabolism
Monocarboxylate transporters (MCT) remove excess lactate generated by tumor cells using the glycolytic pathway under aerobic conditions (“Warburg effect”). Two isoforms, MCT1 and MCT4, are overexpressed in cancer and are potential therapeutic targets. Beloueche-Babari and colleagues utilized in vitro and in vivo assays to assess relevance of the MCT1 inhibitor AZD3965 on metabolism. In both human lymphoma and colon carcinoma cells, AZD3965 enhanced MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism were increased following treatment with AZD3965. This in turn enhanced oxidative pyruvate dehygrogenase and anaplerotic pyruvate carboxylase fluxes. Under drug stress, cell survival was maintained by increased mitochondrial metabolism. Coadministration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099 counteracted these effects. In mouse xenograft models of human lymphoma, bioenergetics were improved following treatment with AZD3965. Thus, the authors identified novel metabolic consequences of MCT1 inhibition with potential therapeutic and pharmacodynamic purposes.
Super-Enhancer Landscape in AML
Somatic mutation analysis has been used for the classification of tumors into distinct subtypes and to discover putative oncogenic drivers. McKeown and colleagues profiled the super-enhancer landscape of 66 patients with acute myeloid leukemia (AML) and identified six different AML subgroups that were largely classified orthogonal to their somatic mutations. Super-enhancer–specific transcription factor networks were inferred, leading to the identification in a subset of patients with AML of a super-enhancer at the retinoic acid receptor alpha (RARα) locus with concomitant high mRNA expression of RARα. Further, such AML tumors were especially vulnerable to the RARα agonist SY-1425, resulting in increased cell differentiation and loss of proliferation. Thus, a subset of patients with AML with a super-enhancer at the RARα locus respond robustly to retinoids.
Perineural Invasion Directs Angiogenesis
Perineural invasion is a poor prognostic factor in many epithelial cancers. Zahalka and colleagues follow up on work demonstrating that autonomic nerve fibers in the prostate gland regulate prostate cancer. Here, they show that inhibition of adrenergic nerve activity altered tumor endothelial cell metabolism towards greater utilization of oxidative phosphorylation, preventing the angiogenic switch from hyperplasia to highly vascularized aggressive prostate cancer. Specifically, deletion of the gene encoding the β2-adrenergic receptor (Adrb2) increased oxidative phosphorylation in endothelial cells via increased expression of the mitochondrial cytochrome c oxidase assembly factor COA6, inhibiting angiogenesis. The angiogenic switch phenotype could be rescued in vivo by conditional codeletion of Cox10, cytochrome IV oxidase assembly factor, preventing the transition to oxidative phosphorylation in endothelial cells induced by Adrb2 knockout. Thus, cotargeting this novel neural-endothelial cell axis may improve outcomes.
Faithful Preclinical Modeling of H3K27M Diffuse Midline Glioma
Childhood midline malignant diffuse gliomas frequently harbor K27M hotspot mutations in histones H3.1 or H3.3. Panthania and colleagues introduced H3.3K27M in the mouse germ line and observed an early embryonic lethal phenotype. Introducing the mutation postnatally on a Trp53 mutant background did not yield tumors. Using in utero electroporation, they introduced H3.3K27M and Trp53 at the peak of neurogenesis in GFAP and Nestin-expressing cells (embryonic day 12.5-13.5). Diffuse high-grade tumors arose at high penetrance at 8 months of age. ATRX loss in addition to H3.3K27M and Trp53 mutation shortened latency, with PDGFRA further reducing latency. Cross-species genomics and epigenomics confirmed similarity to human midline diffuse glioma. This study highlights the importance of correct timing and anatomical compartment to generate preclinical models of pediatric brain tumors.
Aligned Fibronectin Guides Cancer Cell Invasion
Erdogan and colleagues demonstrate that cancer-associated fibroblasts (CAF) generate an aligned fibronectin-rich matrix to induce migration of cancer cells. Mechanistically, this stemmed from CAF's excessive production of matrix proteins, their strong actomyosin contractility, and traction forces exerted on the secreted matrix via the fibronectin binding α5β1 integrin. The proinvasive characteristics of CAF-generated matrix were not cancer type specific. In regions of invasion, cancer cells and surrounding α-SMA positive fibroblasts were surrounded by well-organized, linear fibronectin fascicles, rare in normal tissues. These data indicate common invasion mechanisms shared by different cancer types in vivo. Targeting this pathway is possible clinically, because CAF matrix generation is sensitive to inhibition of PDGFR and α5β1 integrin, both molecules currently targeted in clinical trials.
Note: Breaking Advances 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.