Selected Articles from This Issue

Deregulation of c-MYC signaling via heterodimerization with its binding partner MAX is a major contributor to tumorigenesis and aggressive cancer phenotypes. In this study, Llabata and colleagues identify MGA, which is significantly mutated in lung cancer, as a negative regulator of the MYC pathway. Protein interaction studies and cistrome analysis of MYC and MGA revealed that both proteins bound to MAX in a mutually exclusive manner and exerted opposing effects on MYC target gene expression and cell proliferation. Specifically, MGA:MAX was shown to bind to the regulatory regions associated with key cancer-associated genes normally activated by MYC, recruiting the transcriptionally repressive PCGF6-PRC1 complex with which MYC was not associated. Loss of MGA function or expression was shown to hyperactivate MYC signaling, thus positioning MGA as a key negative regulator of this axis and constituting a novel regulatory mechanism controlling proliferative signaling in lung adenocarcinoma.

BRAF is a well-characterized member of the Ras/Raf/Mek/Erk MAp. signaling cascade and a known proto-oncogene in a variety of different cancers. BRAF gene fusions also occur at low penetrance across many different cancer types, consisting of a number of different 5′ partners that fuse with the 3′ BRAF serine/threonine kinase domain. These fusions replace the amino-terminal BRAF auto-inhibitory region and thus render the fusion product constitutively active. However, the precise role and activity of these different fusion products is unknown. Here, Stangl and colleagues demonstrate that the identity of the 5′ partner exerts various effects on the subcellular localization and signaling activity of each of the unique fusion products, rendering cells differentially susceptible to downstream Mek and Erk inhibitors. However, all of the fusion configurations tested promoted resistance to upstream modulation of EGFR activity, suggesting that BRAF fusions of all types should constitute an exclusion criterion for the use of EGFR-targeted therapy in the clinic.

Cancer cells alter their metabolism in order to meet resource demands, thereby forming a reliance on certain metabolic pathways to support their continued proliferation and expansion. This is particularly true for metastatic subclones of a tumor, which must adapt to a different set of microenvironmental conditions upon establishing a lesion at a distant site. In this study, Li and colleagues performed metabolic profiling of breast cancer cells, identifying serine hydroxymethyltransferase 2 (SHMT2) as a critical mediator of metastatic cancer cell metabolism. As a rate-limiting enzyme in the purine biosynthetic pathway, mitochondrial SHMT2 was shown to be essential for establishment of metastases in vivo, in addition to controlling tumor growth. Accordingly, SHMT2 expression was increased in metastases relative to primary tumors from several different cancers. Taken together, these data suggest that the mitochondrial serine and one-carbon unit metabolic pathway may represent an attractive target to impede the progression of certain cancer types.

Hypoxic signaling has been associated with resistance to a variety of chemotherapeutics, but the mechanisms underlying this effect are varied and poorly understood. Here, Indira Chandran and colleagues show that tumor hypoxia redistributes caveolin-1 phosphorylation, leading to defects in HER2 receptor endocytosis and reduced efficacy of HER2-targeted therapy with the antibody-drug conjugate trastuzumab-emtansine (T-DM1). Similarly, both phosphorylation-deficient caveolin-1 and depletion of caveolin-1 rendered cells unable to mediate HER2 internalization, thus impeding T-DM1 uptake. Importantly, HER2 expression was not affected by caveolin-1 manipulation, suggesting that the two proteins are regulated separately and that the effects observed were restricted to receptor internalization defects. Taken together, the data identify caveolin-1 as a mediator of resistance to T-DM1 therapy and nominate tumor oxygenation as a key determinant of therapeutic efficacy in this context.