References of "Ullmann, Pit 50003236"
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See detailTumor suppressor miR-215 counteracts hypoxia-induced colon cancer stem cell activity
Ullmann, Pit UL; Nurmik, Martin UL; Schmitz, Martine UL et al

in Cancer Letters (2019), 450

Cancer stem cells, also known as tumor-initiating cells (TICs), are a population of aggressive and self-renewing cells that are responsible for the initiation and progression of many cancers, including ... [more ▼]

Cancer stem cells, also known as tumor-initiating cells (TICs), are a population of aggressive and self-renewing cells that are responsible for the initiation and progression of many cancers, including colorectal carcinoma. Intratumoral hypoxia, i.e. reduced oxygen supply following uncontrolled proliferation of cancer cells, is thought to support TIC activity by inducing specific hypoxia-responsive mechanisms that are not yet entirely understood. Using previously established and fully characterized patient-derived TIC cultures, we could observe increased sphere and colony formation under hypoxic conditions. Mechanistically, microRNA (miRNA)-profiling experiments allowed us to identify miR-215 as one of the main hypoxia-induced miRNAs in primary colon TICs. Through stable overexpression of miR-215, followed by a set of functional in vitro and in vivo investigations, miR-215 was pinpointed as a negative feedback regulator, working against the TIC-promoting effects of hypoxia. Furthermore, we could single out LGR5, a bona fide marker of non-neoplastic intestinal stem cells, as a downstream target of hypoxia/miR-215 signaling. The strong tumor- and TIC-suppressor potential of miR-215 and the regulatory role of the hypoxia/miR-215/LGR5 axis may thus represent interesting points of attack for the development of innovative anti-CSC therapy approaches. [less ▲]

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See detailIn search of definitions: Cancer-associated fibroblasts and their markers
Nurmik, Martin UL; Ullmann, Pit UL; Rodriguez, Fabien UL et al

in International Journal of Cancer (2019)

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually ... [more ▼]

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various "CAF markers", such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting. [less ▲]

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See detailThe microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis.
Ullmann, Pit UL; Rodriguez, Fabien UL; Schmitz, Martine UL et al

in Cancer research (2018)

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key ... [more ▼]

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-beta) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-beta receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. [less ▲]

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See detailLoss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence
Letellier, Elisabeth UL; Schmitz, Martine UL; Ginolhac, Aurélien UL et al

in British Journal of Cancer (2017), 117(11), 1689-1701

Background: Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognized ... [more ▼]

Background: Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognized to play a major role in trafficking and polarization of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC. Methods: We used a previously established meta-analysis of publicly available gene expression data to analyse the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC. Using laser-microdissected material as well as tissue microarrays from paired human CRC samples, we validated both RNA and protein expression of MYO5B and its known adapter proteins (RAB8A and RAB25) in an independent patient cohort. Finally, we assessed the prognostic value of both MYO5B and its adapter-coupled combinatorial gene expression signatures. Results: The meta-analysis as well as an independent patient cohort study revealed a methylation-independent loss of MYO5B expression in CRC that matched disease progression. Although MYO5B mutations were identified in a small number of patients, these cannot be solely responsible for the common down-regulation observed in CRC patients. Significantly, CRC patients with low MYO5B expression displayed shorter overall, disease- and metastasis-free survival, a trend that was further reinforced when RAB8A expression was also taken into account. Conclusions: Our data identifies MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy. [less ▲]

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See detailMicroRNA regulation of hypoxia-induced tumorigenicity and metastatic potential of colon tumor-initiating cells
Ullmann, Pit UL

Doctoral thesis (2017)

The initiaton and progression of colorectal cancer (CRC), which is the second most common cause of cancer mortality in Western countries, are driven by a subpopulation of highly tumorigenic cells, known ... [more ▼]

The initiaton and progression of colorectal cancer (CRC), which is the second most common cause of cancer mortality in Western countries, are driven by a subpopulation of highly tumorigenic cells, known as cancer stem cells or tumor-initiating cells (TICs). These self-renewing TICs are, to a large extent, responsible for therapy resistance, cancer recurrence, and metastasis formation. TICs are known to extensively interact with their microenvironment and can be influenced by various extrinsic factors, such as inflammatory signaling or tumor hypoxia. Previous expression profiling studies have shown that microRNAs (miRNAs) are involved in the regulation of CRC inititation and metastatic progression. Moreover, specifc miRNAs have been identified as potential mediators of the cellular response to hypoxia. On the other hand, the molecular mechanisms that link hypoxia, miRNA expression, colon TIC regulation, and CRC progression, remain poorly understood. Thus, the main objectives of this work were to analyze the effects of hypoxia on the miRNA expression of colon TICs and to identify miRNAs that regulate metastasis initiation. In a first phase, we generated and thoroughly characterized different stable TIC-enriched spheroid cultures (SCs), both from CRC cell lines and from primary patient material. Each established SC was thereby shown to display key TIC properties, including substantial plasticity, in vitro and in vivo self-renewal capacity and, most importantly, extensive tumorigenic potential. Moreover, the individual SCs displayed increased chemoresistance capacity, compared to adherent counterpart cultures. Taken together, we could demonstrate that the spheroid system is a suitable model to study colon TICs, thereby laying the methodological foundation for the following subparts of this project. In a second step, we studied the influence of hypoxia on the miRNA expression profile of our established SCs. MiR-210-3p was thereby identified as the miRNA with the strongest response to hypoxia. Importantly, both hypoxic culture conditions and stable overexpression of miR-210 were shown to promote in vitro and in vivo self-renewal capacity of our colon TIC-enriched cultures. Moreover, by promoting lactate production and by repressing mitochondrial respiration, miR-210 was found to trigger the metabolic reprogramming of colon TICs towards a glycolytic and aggressive phenotype. Finally, we studied the role of miRNAs in the context of TIC-driven metastasis formation. By comparing primary tumor- and lymph node metastasis-derived SCs, we were able to identify the miR-371~373 cluster as an important regulator of tumorigenic and metastatic potential. Stable overexpression of the entire miR-371~373 cluster, followed by gene and protein expression analysis, enabled us to uncover the transforming growth factor beta receptor II (TGF-βRII) and the inhibitor of DNA binding 1 (Id1) as miR-371~373 cluster-responsive proteins. Most importantly, different sphere, tumor, and metastasis formation assays revealed that the miR-371~373/TGF-βRII/Id1 signaling axis regulates the self-renewal capacity and metastatic colonization potential of colon TICs. Taken together, our findings emphasize the strong plasticity of colon TICs and clearly illustrate that miRNAs can act as potent modulators of essential TIC properties. Accordingly, we could show that miR-210 and the miR-371~373 cluster are involved in metabolic reprogramming of TICs and in the regulation of metastasis formation, respectively. Altogether, our study contributes to a better understanding of the molecular mechanisms that drive TIC-induced tumor progression and may provide indications for interesting miRNA biomarker candidates and target molecules for future TIC-specific therapies. [less ▲]

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See detailTumor-Initiating Cells: a criTICal review of isolation approaches and new challenges in targeting strategies
Baig, Komal UL; Ullmann, Pit UL; Haan, Serge UL et al

in Molecular Cancer (2017)

Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self ... [more ▼]

Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self-renewal and tumorigenic properties as well as their resistance to conventional therapies. Despite significant advances in TIC biology, their isolation and identification remain largely disputed and incompletely established. In this review, we discuss the latest developments in isolation and culturing approaches of TICs, with focus on colorectal cancer (CRC). We feature recent findings on TIC-relevant signaling pathways and the metabolic identity of TICs, as well as their current clinical implications. Lastly, we highlight the influence of inter- and intra-tumoral heterogeneity on TIC function and targeting approaches. [less ▲]

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See detailHypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production
Ullmann, Pit UL; qureshi-baig, komal; Rodriguez, Fabien UL et al

in Oncotarget (2016)

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor ... [more ▼]

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor-initiating cells (TICs). To better understand the mechanism of hypoxia-induced TIC activation, we set out to study the role of hypoxia-responsive miRNAs in recently established colon cancer patientderived TICs. We were able to show that low oxygen concentrations consistently lead to the upregulation of miR-210 in different primary TIC-enriched cultures. Both stable overexpression of miR-210 and knockdown of its target gene ISCU resulted in enhanced TIC self-renewal. We could validate the tumorigenic properties of miR- 210 in in vivo experiments by showing that ectopic expression of miR-210 results in increased tumor incidence. Furthermore, enhanced miR-210 expression correlated with reduced TCA cycle activity and increased lactate levels. Importantly, by blocking lactate production via inhibition of LDHA, we could reverse the promoting effect of miR-210 on self-renewal capacity, thereby emphasizing the regulatory impact of the glycolytic phenotype on colon TIC properties. Finally, by assessing expression levels in patient tissue, we could demonstrate the clinical relevance of the miR-210/ISCU signaling axis for colorectal carcinoma. Taken together, our study highlights the importance of hypoxia-induced miR-210 in the regulation of colon cancer initiation. [less ▲]

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See detailWhat Do We Learn from Spheroid Culture Systems? Insights from Tumorspheres Derived from Primary Colon Cancer Tissue.
Baig, Komal UL; Ullmann, Pit UL; Rodriguez, Fabien UL et al

in PLoS ONE (2016), 11

Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the ... [more ▼]

Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the fact that the identification and culturing of TICs is still a subject of extensive debate. Floating three-dimensional spheroid cultures (SC) that grow in serum-free medium supplemented with growth factors are supposed to be enriched in TICs. We generated SC from fresh clinical tumor specimens and compared them to SC isolated from CRC cell-lines as well as to adherent differentiated counterparts. Patient-derived SC display self-renewal capacity and can induce serial transplantable tumors in immuno-deficient mice, which phenotypically resemble the tumor of origin. In addition, the original tumor tissue and established SC retain several similar CRC-relevant mutations. Primary SC express key stemness proteins such as SOX2, OCT4, NANOG and LGR5 and importantly show increased chemoresistance ability compared to their adherent differentiated counterparts and to cell line-derived SC. Strikingly, cells derived from spheroid or adherent differentiating culture conditions displayed similar self-renewal capacity and equally formed tumors in immune-deficient mice, suggesting that self-renewal and tumor-initiation capacity of TICs is not restricted to phenotypically immature spheroid cells, which we describe to be highly plastic and able to reacquire stem-cell traits even after long differentiation processes. Finally, we identified two genes among a sphere gene expression signature that predict disease relapse in CRC patients. Here we propose that SC derived from fresh patient tumor tissue present interesting phenotypic features that may have clinical relevance for chemoresistance and disease relapse and therefore represent a valuable tool to test for new CRC-therapies that overcome drug resistance. [less ▲]

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