Highlights of This Issue

DOI: Published November 2016

NSCLC Tumors Endocytotically Engulf ATP

Qian et al. Page 1087

Using fluorescence microscopy coupled with inhibitors/siRNA knockdowns, this study demonstrates that extracellular ATP is actively internalized by cancer cells through micropinocytosis and other endocytic processes in vitro and in vivo. This ATP internalization elevates the intracellular ATP levels by more than 50% within 24 hours. These new findings provide insight into key questions of the Warburg effect: why cancer cells upregulate glycolysis and how cancer cells manage to meet their energy (ATP) requirements even under hypoxic conditions. This ATP sharing among cancer cells performs multiple and previously unrecognized important functions and offers a novel anticancer target.

AR is Required for ER Activity in Breast Cancer

D'Amato et al. Page 1054

Development of new androgen receptor (AR) inhibitors and recognition that AR is expressed in approximately 80% of all breast cancers (BCa) has led to revived interest in AR as a therapeutic target. However, the role of AR in estrogen receptor-positive (ER+) BCa is controversial. In multiple ER+/AR+ cell lines and patient-derived xenograft (PDX) models, the AR antagonist enzalutamide decreased estrogen-induced tumor growth, synergized with anti-estrogens tamoxifen and fulvestrant, and inhibited viability of tamoxifen-resistant tumors. Mechanistically, anti-androgens that inhibit AR nuclear localization diminished ER chromatin binding following estradiol treatment. The preclinical data support further testing of new generation AR antagonists in ER+ BCa, alone or in combination with ER-targeting agents, particularly in tumors with high AR or those resistant to anti-estrogens.

Fbw7 Negatively Regulates CDX2 Stability

Kumar et al. Page 1097

Deregulated expression of CDX2 has differential effects ranging from tumor suppressive to oncogenic in colorectal cancers; however, the underlying mechanism has remained unexplored. Kumar and colleagues demonstrate that the E3 ubiquitin ligase, Fbw7, regulates CDX2 protein stability and functions in a GSK3β-dependent manner where phosphorylation of CDX2 at two potential Cdc4 Phosphodegron (CPD) motifs primes it to be recognized and ubiquitinated by Fbw7. Very importantly, the data also show that Fbw7-mediated ubiquitination of CDX2 can be antagonized by USP28. Collectively, these data provide a detailed molecular mechanism of CDX2 regulation by the Fbw7-GSK3β-USP28 axis which can be targeted in colorectal cancer for better therapeutics.

MMP9 Ablation-induced Invasive Growth of PDAC

Grünwald et al. Page 1147

The advent of new selective MMP9-inhibtory agents preluded a renaissance of MMP9 as a therapeutic target for aggressive gastrointestinal tumors. Here, a clinically relevant pancreatic cancer mouse model was used to determine the consequences of genetic ablation of MMP9. Selective long-term loss of MMP9 functions, dramatically promoted invasive growth of pancreatic cancer triggered by elevated systemic levels of IL-6. Abrogation of MMP9-dependent SCF-signaling in the bone marrow led it to secrete IL-6, which activated the pro-invasive IL-6/IL6R/STAT3 axis in pancreatic tumor cells. This fatal inter-organ communication represents an important caveat for the use of systemically administered selective MMP9 inhibitors in cancer.