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Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3×10−10), CCL2/IL13 expression (p<10−109) and TAM infiltration (p<10−96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment. Cancer develops when cells in the body gain mutations that allow them to grow and divide rapidly and uncontrollably. As the disease progresses these cancer cells develop the ability to spread around the body. This process of spreading, called metastasis, is responsible for most cancer-related deaths in humans, but no current treatments target it. Mutations that increase the levels of two proteins known as MYC and TWIST1 in cells cause many human cancers. In healthy adult cells, normal levels of MYC and TWIST1 act as key regulators that switch thousands of genes on or off. TWIST1 is known to control the movement and spread of cells in the embryo. However, it is not known how MYC and TWIST1 work together to promote the metastasis of cancer cells. To address this question, Dhanasekaran, Baylot et al. used mice to investigate the roles of MYC and TWIST1 in the metastasis of cancer cells. The experiments showed that these two proteins work together to reprogram mouse cancer cells to release signal molecules known as cytokines. These molecules convert immune cells known as macrophages to a tumor-friendly state that allows cancers cells to spread around the body. Inhibiting two cytokines known as CCL2 and IL13 prevented the cancer cells from moving. Further experiments analyzed tumor samples from around 10,000 human patients with 33 different cancers. This revealed that patients that had higher levels of MYC and TWIST1 proteins in their tumors also had increased levels of CCL2 and IL13, more activated macrophages and were less likely to recover from their cancer. The findings of Dhanasekaran, Baylot et al. suggest that MYC and TWIST1 may instigate metastasis in many human cancers, and therapies targeting specific cytokines may prevent these cancers from spreading around the body. Furthermore, screening blood for the levels of cytokines may help to identify the cancer patients who would benefit from such therapies.

p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK−DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus. p27/cJun up-regulates TGFB2 to drive metastasis in vivo. Global analysis of p27 and cJun chromatin binding and gene expression shows that cJun recruitment to many target genes is p27 dependent, increased by p27 phosphorylation, and activates programs of epithelial–mesenchymal transformation and metastasis. Finally, human breast cancers with high p27pT157 differentially express p27/cJun-regulated genes of prognostic relevance, supporting the biological significance of the work.

The angiogenic factor, VEGFA, is a therapeutic target in ovarian cancer (OVCA). VEGFA can also stimulate stem‐like cells in certain cancers, but mechanisms thereof are poorly understood. Here, we show that VEGFA mediates stem cell actions in primary human OVCA culture and OVCA lines via VEGFR2‐dependent Src activation to upregulate Bmi1, tumor spheres, and ALDH1 activity. The VEGFA‐mediated increase in spheres was abrogated by Src inhibition or SRC knockdown. VEGFA stimulated sphere formation only in the ALDH1 + subpopulation and increased OVCA‐initiating cells and tumor formation in vivo through Bmi1. In contrast to its action in hemopoietic malignancies, DNA methyl transferase 3A (DNMT3A) appears to play a pro‐oncogenic role in ovarian cancer. VEGFA‐driven Src increased DNMT3A leading to miR‐128‐2 methylation and upregulation of Bmi1 to increase stem‐like cells. SRC knockdown was rescued by antagomir to miR‐128. DNMT3A knockdown prevented VEGFA‐driven miR‐128‐2 loss, and the increase in Bmi1 and tumor spheres. Analysis of over 1,300 primary human OVCAs revealed an aggressive subset in which high VEGFA is associated with miR‐128‐2 loss. Thus, VEGFA stimulates OVCA stem‐like cells through Src‐DNMT3A‐driven miR‐128‐2 methylation and Bmi1 upregulation. Synopsis VEGFA is not only a key mediator of angiogenesis during tumor progression, but can also act to expand the population of ovarian cancer‐initiating cells with stem‐like properties. VEGFA increases sphere formation and ALDH1 activity of ovarian cancer cells in vitro and stimulates ovarian tumor‐initiating cells in vivo . VEGFA rapidly activates VEGFR2 and Src to upregulate DNMT3 expression. DNMT3A plays a pro‐oncogenic role to methylate miR‐128‐2 leading to Bmi1 and OVCA stem‐like cell upregulation. High VEGFA and decreased miR‐128‐2 associate with poor ovarian cancer outcome. Graphical Abstract VEGFA is not only a key mediator of angiogenesis during tumor progression, but can also act to expand the population of ovarian cancer‐initiating cells with stem‐like properties.

In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC , the Notch ligand JAG1 , and ANGPTL4 . p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12 . Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues. Cancer stem cells (CSCs) have important roles in tumour initiation, metastasis and treatment resistance. Here, the authors show that C-terminally phosphorylated p27, together with STAT3, mediates the transcriptional regulation of CSC expansion, increasing cancer formation and metastasis in preclinical breast cancer models.

Distant metastases are the leading cause of breast cancer related death. It is important to understand how the metastatic process is regulated in order to develop new therapies that would oppose metastasis and improve cancer outcome. Initiation of metastasis requires cell invasion and escape from the primary tumor into the vasculature followed by colonization of secondary sites. Tumor invasion and intravasation are enabled by the epithelial mesenchymal transition (EMT), a process in which epithelial cells lose polarity and intracellular adhesion and acquire motility and invasiveness. This thesis work has revealed novel mechanisms whereby cancer metastasis is regulated via induction of EMT. First, this thesis work provides a novel mechanism whereby VEGFA promotes metastasis through activation of EMT. VEGFA is best known as an angiogenic agent, but it also promotes cancer invasion and metastasis through mechanisms that are not fully understood. Our prior work showed VEGFA mediates cancer stem cell (CSC) expansion via induction of SOX2, a key stem cell driver in breast cancer models. Here, we showed VEGFA rapidly upregulates SOX2, leading to SNAI2 induction and EMT. Sox2 downregulates miR-452, a novel metastasis suppressor, that we show directly targets the SNAI2 3’ UTR. VEGFA induction of SOX2 leads to loss of miR452 and upregulation of Slug, driving EMT and metastasis in breast cancer models. Second, we also uncovered a new mechanism whereby T157 and T198-phosphorylated, deregulated p27 contributes to cancer metastasis. In normal cells, p27 regulates cell cycle and functions as an atypical tumor suppressor. While p27 is rarely completely lost, it is frequently deregulated through either excess degradation or through key C-terminal phosphorylations in human cancers. We and others have previously identified an oncogenic role for p27 in motility, invasion and metastasis resulting from these C-terminal phosphorylations. Here we showed that p27CK-DD induced EMT and enhanced metastatic potential of breast cancer cell lines. Knockdown of p27 in highly metastatic EMT-transformed cell lines with high levels of p27pT157pT198 (p27pTpT) reverted EMT and impaired metastatic potential. Mechanistically, we provides evidence for p27 as a transcriptional co-regulator of cJun. We showed that C-terminally phophorylated p27 binds and activates cJun, and forms a complex with cJun at an enhancer region upstream of the TGF-β2 gene to induce TGF-β2 and EMT. My PhD data identify novel pathways in which Sox2, upregulated by VEGFA, contributes to activation of EMT and metastasis through Slug. Furthermore, this thesis work reveals an oncogenic function of p27 to promote tumor progression through EMT via cJun-mediated TGF-β2 induction. Since treatment of metastasis is the final therapeutic frontier, it is hoped that mechanistic insights into acquisition of metastatic potential through EMT may ultimately generate new strategies for opposing metastasis and improving outcome of cancer.