Defining the Hallmarks of Metastasis

Welch, Danny R.; Hurst, Douglas R.

doi:10.1158/0008-5472.can-19-0458

Cited by 532 publications

(479 citation statements)

References 249 publications

(265 reference statements)

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“…We propose that CCM1 is an important regulator of the YAP/TAZ and AR signaling in PCa cells. That stated, our evidence indicates that despite the concomitant activation of multiple pro-tumoral signaling pathways, suppression of CCM1 ameliorated representative metastatic hallmarks, namely motility, invasion and survival (43), in multiple types of both androgen-responsive and androgen-non-responsive metastatic PCa cells. CCM1 may not be sufficient to induce tumorigenesis, but it appears to unleash the oncogenic potential of multiple cellular signals, promoting cancer progression including the invasiveness Based on genetic aberrations of AR or the increased synthesis of androgens (in the tumor microenvironment [TME]) or adrenal androgen precursors, it has been reported that AR expression is increased (44) and that AR signaling is consistent with the castration level of androgens in patients with mCRPC.…”

Section: Discussionmentioning

confidence: 62%

Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

Kim

Park

Lee

et al. 2020

Preprint

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Enhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZbinding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the PLK1-mediated suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. We also revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. Our findings highlight the importance of CCM1-DDX5-PLK1-YAP/TAZ signaling in the metastasis of prostate cancer cells. 4 Statement of SignificanceOur analysis of CCM1 expression and function represents a candidate predictive biomarker for prostate cancer metastasis and provides an evidence that abnormality of CCM1 can be pathogenic in prostate cancer. Importantly, CCM1 regulation of metastasis progression appears to a common molecular event in metastatic prostate cancer cells arising in disparate genetic backgrounds.

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Section: Discussionmentioning

confidence: 62%

Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

Kim

Park

Lee

et al. 2020

Preprint

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“…Recent results extend the risk for metastasis to 10 years postpartum, which makes the percentage of young breast cancer patients who are considered postpartum and as such at high risk for metastasis nearly 50%(26). A recent publication by Welch and Hurst defines the hallmarks of metastasis as motility and invasion, modulation of the microenvironment, plasticity and colonization(27). Here, using pre-clinical models, we identify potential tumor intrinsic and extrinsic roles for SEMA7A in promotion of PPBC growth including invasion, modulation of the microenvironment, survival in hostile environments such as the circulation, and colonization.…”

Section: Discussionmentioning

confidence: 99%

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Tarullo

Hill

Hansen

et al. 2019

Preprint

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Breast cancer (BC) remains the second leading cause of cancer related deaths in women in the US --mainly due to metastatic disease. Thus, understanding how BC progresses is of the utmost importance to developing new strategies to block metastasis. Young women diagnosed with BC generally have poor prognosis due to increased rates of metastasis. Additionally, women who are within 5 years of most recent child-birth at diagnosis are ~3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum breast cancers (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression and metastasis. Semaphorin 7a (SEMA7A) is a unique member of the Semaphorin family as it is the only GPI-anchored member that can be shed into the extracellular environment. Our published results show that SEMA7A expression is associated with decreased overall survival in BC patient cohorts and revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis all of which are also increased in pre-clinical models of PPBC. However, whether primary SEMA7A driver PPBC progression remains largely unexplored. We utilized a pre-clinical of PPBC with breast cancer cells where we silenced or overexpressed SEMA7A. Our results show that silencing of SEMA7A decreases tumor growth in postpartum hosts while overexpression increases growth in nulliparous hosts to rates closer to those observed in postpartum hosts. Further, we show that SEMA7A effects multiple pro-metastatic tumor attributes such as cell survival, tumor associated COX-2 expression, fibronectin deposition, and fibroblast-mediated collagen deposition in the tumor microenvironment regardless of whether the host is nulliparous or postpartum. Finally, we show that co-expression of SEMA7A/Collagen/COX2/FN mRNA predicts for increased metastasis in breast and ovarian cancer cohorts. These studies suggest SEMA7A as a key mediator of general BC progression and that targeting SEMA7A alone or in combination may open avenues for novel therapeutic strategies to prevent BC progression to metastasis. INTRODUCTION:Postpartum breast cancers (PPBC), or breast cancers diagnosed within 5-10 years of last childbirth, are nearly three times as likely to become metastatic and result in death from breast cancer 1-3 . Specifically, PPBC patients diagnosed within five years of last competed pregnancy exhibit 70% distant metastasis free five-year survival (DMFS) rates 1 that are further decreased to 50% after ten years 2 . Using this definition, PPBC may account over half of breast cancers diagnosed in women aged <45 in two independent cohorts. Using a pre-clinical model of PPBC we have shown that noninvasive breast tumor cells, MCF10DCIS, become invasive and metastatic if they are implanted into mouse mammary tissues during the normal physiological process of postpartum mammary gland involution 4 . The MCF10DCIS model closely resembles ductal carcinoma in situ (DCIS) and progresse...

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“…Metastasis is thought to be the ultimate manifestation of a neoplastic cell's evolution towards becoming autonomous from the host, and remains the main cause of cancer-related death 27,28 .…”

Section: Introductionmentioning

confidence: 99%

“…In fact, cure of most cancers is probable whenever diagnosis occurs before cells have spread beyond the tissue of origin; otherwise, cancer is often referred to as incurable [33][34][35] . According to Welch and Hurst 28 , the four hallmarks of metastasis are motility and invasion, modulate microenvironment, plasticity and colonization. Regarding mechanisms of HIF-mediated metastasis, hypoxia and activation of HIF signaling influence multiple steps within the metastatic cascade, including invasion and migration, intravasation and extravasation, and establishment of the premetastatic niche, as well as survival and growth at the distant site 24,36,37 .…”

Section: Introductionmentioning

confidence: 99%

Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

López‐Cortés

Guevara-Ramírez

Guerrero

et al. 2020

Preprint

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Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia.Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.

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Defining the Hallmarks of Metastasis

Cited by 532 publications

References 249 publications

Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

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