The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.

Cellular programs coupled to cycles of epithelial–mesenchymal transitions (EMTs) play critical roles during embryogenesis, as well as during tissue development, remodeling, and repair. Research over the last decade has established the importance of an ever-expanding list of master EMT transcription factors, whose activity is regulated by STAT3 and function to stimulate the rapid transition of cells between epithelial and mesenchymal phenotypes. Importantly, inappropriate reactivation of embryonic EMT programs in carcinoma cells underlies their metastasis to distant organ sites, as well as their acquisition of stem cell-like and chemoresistant phenotypes operant in eliciting disease recurrence. Thus, targeted inactivation of master EMT transcription factors may offer new inroads to alleviate metastatic disease. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of STAT3 during its regulation of EMT programs in human carcinomas.

Background: Cells perceive their environment through soluble growth factors and in response to extracellular matrix. Results: STAT3 signaling can be activated by multiple pathways during breast cancer progression. Conclusion: Fibronectin:STAT3 signaling promotes three-dimensional outgrowth of breast cancer cells. Significance: This study demonstrates a novel mechanism by which STAT3 becomes activated by the extracellular matrix independent of the canonical EGF receptor signaling network.

Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies. SignificanceSCNCs are aggressive and histologically similar across tissue types, and no effective treatment modalities are available. Lung and prostate adenocarcinomas can transdifferentiate to SCNCs in response to targeted therapy. This has important consequences in that SCNCs, once considered rare, may become increasingly common with the emergence of resistance cases from targeted therapies. Here we define molecular signatures for SCNCs, and we find that SCNCs share similar drug and RNAi vulnerabilities with blood cancers. Our results guide the detection of SCN-like cases in the clinic, and support the exploration of treatments for SCNCs that mimic treatments for blood cancers.

Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan‐cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis‐defined CNA signatures are predictive of glycolytic phenotypes, including 18F‐fluorodeoxy‐glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer‐linked metabolic enzymes. A pan‐cancer and cross‐species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer‐driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.

Filopodia formation is positively regulated by β3 integrin–EGFR cross-talk, which regulates p190RhoGAP activity and localization in normal mouse mammary gland epithelial cells.

Numerous studies by our lab and others demonstrate that epidermal growth factor receptor (EGFR) plays critical roles in primary breast cancer (BC) initiation, growth and dissemination. However, clinical trials targeting EGFR function in BC have lead to disappointing results. In the current study we sought to identify the mechanisms responsible for this disparity by investigating the function of EGFR across the continuum of the metastatic cascade. We previously established that overexpression of EGFR is sufficient for formation of in situ primary tumors by otherwise nontransformed murine mammary gland cells. Induction of epithelial-mesenchymal transition (EMT) is sufficient to drive the metastasis of these EGFR-transformed tumors. Examining growth factor receptor expression across this and other models revealed a potent downregulation of EGFR through metastatic progression. Consistent with diminution of EGFR following EMT and metastasis EGF stimulation changes from a proliferative to an apoptotic response in in situ versus metastatic tumor cells, respectively. Furthermore, overexpression of EGFR in metastatic MDA-MB-231 BC cells promoted their antitumorigenic response to EGF in three dimensional (3D) metastatic outgrowth assays. In line with the paradoxical function of EGFR through EMT and metastasis we demonstrate that the EGFR inhibitory molecule, Mitogen Induced Gene-6 (Mig6), is tumor suppressive in in situ tumor cells. However, Mig6 expression is absolutely required for prevention of apoptosis and ultimate metastasis of MDA-MB-231 cells. Further understanding of the paradoxical function of EGFR between primary and metastatic tumors will be essential for application of its targeted molecular therapies in BC.