Pan-Cancer Analysis Demonstrates a Cost to Diversity
Andor and colleagues investigated intratumor heterogeneity (ITH) across 12 cancer types. The total number of clones within a tumor and the fraction of the tumor metagenome affected by copy number variation (CNV) were estimated based on somatic single-nucleotide variants and CNVs across 1,165 primary tumor samples. ITH was common with an average of four clones detected per tumor. Fewer than 20% of tumors contained a single clone. Clones with specific mutated driver genes tended to have a similar characteristic size across tumor types. More than two but no more than five clones were associated with poor prognosis across cancer types. Furthermore, using CNV to indicate genomic instability, CNV abundance between 50–75% was associated with poor survival in 11 of 12 tumors types. Thus, diverse cancers show a similar optimal degree of genomic instability.
HOXA5 Inhibits WNT Signaling in CRC
Ordóñez-Morán and colleagues identified the homeobox transcription factor Hoxa5 as highly expressed in differentiated cells of intestinal villi relative to WNT-dependent stem cells of the crypt. Hoxa5 affected expression of WNT target gene Myc. Increased expression of HOXA5 in organoids affected expression of the WNT target gene Myc, resulting in decreased LGR5+ stem cells/self-renewal and increased differentiation, phenocopying β-catenin (CTNNB1) gene deletion. Increased expression of HOXA5 in patients with colorectal cancer (CRC) enriched for relapse-free survival. While parental CRC cells initiated tumors and metastases in mice, those expressing HOXA5 showed reduced tumor growth and metastases. Further, HOXA5 expression in CRC could be reactivated by retinols, reducing the abundance of cancer stem cells and attenuating progression. Thus, retinoid treatment represents a potential new therapeutic agent to treat CRC.
To Metastasize or Not to Metastasize: EMT Is in Question
Independent groups using genetically engineered mouse models (GEMM) of breast or pancreatic adenocarcinoma (PDA) report that epithelial-mesenchymal transition (EMT) intermediates Twist1, Snai1, and miR-200 were required neither for tumor development nor for metastasis. Using complimentary in vitro tumor spheroid assays, in vivo experimental metastasis assays, and cell lineage tracing, both groups suggested that PDA and breast cancer cells with epithelial phenotypes were still competent for metastasis. Another concordant finding was that EMT conferred chemoresistance to gemcitabine or cyclophosphamide. EMT-dependent chemoresistance in these GEMMs resulted from suppression of cancer cell proliferation and regulation of chemotherapy transporters and metabolizing gene products. These provocative in vivo findings suggest caution in applying anti-EMT therapeutics to prevent metastases, although such agents may have roles in therapy resistance.
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527:525–30.
LF3 Has Anticancer Properties
The Wnt/β-catenin signaling contributes to initiation and progression of cancer, and is an attractive target for therapy. Using high-throughput screening, Fang and colleagues assessed small molecules that could disrupt a key step: interaction of β-catenin with the transcription factor TCF4. The authors identified LF3, a 4-thioureido-benzenesulfonamide derivative, as a robust inhibitor, with a core structure essential for activity. LF3 blocked Wnt/β-catenin signaling in cells with high endogenous WNT activity and also suppressed motility, cell cycle progression, and expression of WNT target genes. LF3 did not cause cell death or interfere with cadherin-mediated cell-cell adhesion. Of importance, LF3 could block the self-renewal capacity of cancer stem cells and reduced tumor growth while inducing differentiation in vivo. Thus, LF3 is an inhibitor of canonical WNT signaling resulting in anticancer activity.
Fang L, Zhu Q, Neuenschwander M, Specker E, Wulf-Goldenberg A, Weis WI, et al. A small-molecule antagonist of the β-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Research; Published OnlineFirst December 8, 2015; doi: 10.1158/0008-5472.CAN-15-1519.
Diagnosing Cancer from Platelet RNA
Noninvasive detection and classification of solid tumors from blood samples, “liquid biopsies,” have focused largely on isolating circulating tumor cells and fragments of DNA shed from primary tumors. Best and colleagues profiled platelet RNA from patients with both early (n = 39) and late stage (n = 189) lung, gastrointestinal, brain, and breast cancer, comparing these to platelet RNA from healthy individuals (n = 55). A single drop of blood showed differences in the platelet RNA profiles of cancer-bearing individuals relative to healthy individuals that in cross validation predicted presence of disease with 96% accuracy. Furthermore, specific tumor types were also determined with accuracy from platelet-derived RNAs with further delineation of KRAS and EGFR mutant tumors. Thus, if validated prospectively, platelet-derived RNAs show tremendous potential as predictive biomarkers.
Neutrophils Drive Breast Cancer
Work from Wculek and Malanchi suggests that neutrophils and neutrophil-secreted leukotrienes facilitate a permissive environment for metastatic breast cancer lung colonization. Using antibody depletion, the group demonstrated that neutrophils were required for initiation of lung metastases in MMTV-PyMT breast cancers. Neutrophils enriched the population of cancer cells at the premetastatic niche. Leukotrienes secreted by neutrophils were necessary for breast cancer lung metastasis as shown by conditioned media and direct leukotriene treatment experiments in vitro and later in vivo in both immune competent and deficient mouse models. Genetic or small molecule inhibition of the leukotriene synthesis enzyme ALOX5 greatly attenuated metastatic breast cancer colonization. This work shows that inflammatory cell-induced secretion of leukotrienes at the premetastatic niche enriches for tumorigenic cancer cells to colonize and form lung metastases.
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.