bims-cadres 2023-01-08 papers

Issue of 2023–01–08
seven papers selected by
Rana Gbyli, Yale University

Adv Exp Med Biol. 2022 ;1393 51-64

The Transcription Factors Zeb1 and Snail Induce Cell Malignancy and Cancer Stem Cell Phenotype in Prostate Cells, Increasing Androgen Synthesis Capacity and Therapy Resistance.

Fernanda López-Moncada, Enrique A Castellón, Héctor R Contreras.

Prostate cancer (PCa) incidence has increased during the last decades, becoming one of the leading causes of death by cancer in men worldwide. During an extended period of prostate cancer, malignant cells are androgen-sensitive being testosterone the main responsible for tumor growth. Accordingly, treatments blocking production and action of testosterone are mostly used. However, during disease progression, PCa cells become androgen insensitive producing a castration-resistant stage with a worse prognosis. Overcoming castration-resistant prostate cancer (CRPC) has become a great challenge in the management of this disease. In the search for molecular pathways leading to therapy resistance, the epithelial-mesenchymal transition (EMT), and particularly the transcription factors zinc finger E-box-binding homeobox 1 (Zeb1) and zinc finger protein SNAI1 (Snail), master genes of the EMT, have shown to have pivotal roles. Also, the discovery that cancer stem cells (CSCs) can be generated de novo from their non-CSCs counterpart has led to the question whereas these EMT transcription factors could be implicated in this dynamic conversion between non-CSC and CSC. In this review, we analyze evidence supporting the idea that Zeb1 and Snail induce cell malignancy and cancer stem cell phenotype in prostate cells, increasing androgen synthesis capacity and therapy resistance.

Keywords: Androgens; Cancer stem cells; Prostate cancer; SNAIL; Zeb1; epithelial-mesenchymal transition

DOI: https://doi.org/10.1007/978-3-031-12974-2_2

Cancer Res. 2023 Jan 04. pii: CAN-22-1693. [Epub ahead of print]

YAP-activated SATB2 is a coactivator of NRF2 that amplifies anti-oxidative capacity and promotes tumor progression in renal cell carcinoma.

Juan Jin, Fen Chen, Wenfang He, Li Zhao, Bo Lin, Danna Zheng, Li Chen, Hongchao He, Qiang He.

Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein SATB2 in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated ChIP-seq and ATAC-seq analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer-promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Lastly, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1693

Cell Death Dis. 2023 Jan 02. 14(1): 1

DDX17 induces epithelial-mesenchymal transition and metastasis through the miR-149-3p/CYBRD1 pathway in colorectal cancer.

Gang Zhao, Qijing Wang, Yue Zhang, Rui Gu, Min Liu, Qin Li, Jie Zhang, Hang Yuan, Tianyu Feng, Deqiong Ou, Siqi Li, Shan Li, Kai Li, Chunfen Mo, Ping Lin.

DEAD box helicase 17 (DDX17) has been reported to be involved in the initiation and development of several cancers. However, the functional role and mechanisms of DDX17 in colorectal cancer (CRC) malignant progression and metastasis remain unclear. Here, we reported that DDX17 expression was increased in CRC tissues compared with noncancerous mucosa tissues and further upregulated in CRC liver metastasis compared with patient-paired primary tumors. High levels of DDX17 were significantly correlated with aggressive phenotypes and worse clinical outcomes in CRC patients. Ectopic expression of DDX17 promoted cell migration and invasion in vitro and in vivo, while the opposite results were obtained in DDX17-deficient CRC cells. We identified miR-149-3p as a potential downstream miRNA of DDX17 through RNA sequencing analysis, and miR-149-3p displayed a suppressive effect on the metastatic potential of CRC cells. We demonstrated that CYBRD1 (a ferric reductase that contributes to dietary iron absorption) was a direct target of miR-149-3p and that miR-149-3p was required for DDX17-mediated regulation of CYBRD1 expression. Moreover, DDX17 contributed to the metastasis and epithelial to mesenchymal transition (EMT) of CRC cells via downregulation of miR-149-3p, which resulted in increased CYBRD1 expression. In conclusion, our findings not only highlight the significance of DDX17 in the aggressive development and prognosis of CRC patients, but also reveal a novel mechanism underlying DDX17-mediated CRC cell metastasis and EMT progression through manipulation of the miR-149-3p/CYBRD1 pathway.

DOI: https://doi.org/10.1038/s41419-022-05508-y

Front Oncol. 2022 ;12 1085034

Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance.

Ayenachew Bezawork-Geleta, James Dimou, Matthew J Watt.

A primary brain tumor glioblastoma is the most lethal of all cancers and remains an extremely challenging disease. Apparent oncogenic signaling in glioblastoma is genetically complex and raised at any stage of the disease's progression. Many clinical trials have shown that anticancer drugs for any specific oncogene aberrantly expressed in glioblastoma show very limited activity. Recent discoveries have highlighted that alterations in tumor metabolism also contribute to disease progression and resistance to current therapeutics for glioblastoma, implicating an alternative avenue to improve outcomes in glioblastoma patients. The roles of glucose, glutamine and tryptophan metabolism in glioblastoma pathogenesis have previously been described. This article provides an overview of the metabolic network and regulatory changes associated with lipid droplets that suppress ferroptosis. Ferroptosis is a newly discovered type of nonapoptotic programmed cell death induced by excessive lipid peroxidation. Although few studies have focused on potential correlations between tumor progression and lipid droplet abundance, there has recently been increasing interest in identifying key players in lipid droplet biology that suppress ferroptosis and whether these dependencies can be effectively exploited in cancer treatment. This article discusses how lipid droplet metabolism, including lipid synthesis, storage, and use modulates ferroptosis sensitivity or tolerance in different cancer models, focusing on glioblastoma.

Keywords: brain cancer; cell death; glioma; lipid droplet (LD); lipids; metabolism; therapeutic vulnerabilities

DOI: https://doi.org/10.3389/fonc.2022.1085034

Cancer Res. 2023 Jan 03. pii: CAN-22-2045. [Epub ahead of print]

Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.

Seung Joon Park, Hee Chan Yoo, Eunyong Ahn, Enzhi Luo, Yeabeen Kim, Yulseung Sung, Ya Chun Yu, Kibum Kim, Do Sik Min, Hee Seung Lee, Geum-Sook Hwang, TaeJin Ahn, Junjeong Choi, Seungmin Bang, Jung Min Han.

Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2045

Nat Cell Biol. 2023 Jan 05.

MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.

Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris A Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip M Galbo, Dayle Q Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo.

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal-epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.

DOI: https://doi.org/10.1038/s41556-022-01045-0

Breast Cancer Res. 2023 Jan 03. 25(1): 1

PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.

Saisai Chen, Matt R Paul, Christopher J Sterner, George K Belka, Dezhen Wang, Peining Xu, Amulya Sreekumar, Tien-Chi Pan, Dhruv K Pant, Igor Makhlin, Angela DeMichele, Clementina Mesaros, Lewis A Chodosh.

BACKGROUND: Breast cancer mortality is principally due to recurrent disease that becomes resistant to therapy. We recently identified copy number (CN) gain of the putative membrane progesterone receptor PAQR8 as one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies and occurred in > 50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents.
METHODS: We used orthotopic mouse models to determine whether PAQR8 overexpression or deletion alters breast cancer dormancy or recurrence following therapy. In vitro studies, including assays for colony formation, cell viability, and relative cell fitness, were employed to identify effects of PAQR8 in the context of therapy. Cell survival and proliferation were quantified by immunofluorescence staining for markers of apoptosis and proliferation. Sphingolipids were quantified by liquid chromatography-high resolution mass spectrometry.
RESULTS: We show that PAQR8 is necessary and sufficient for efficient mammary tumor recurrence in mice, spontaneously upregulated and CN gained in recurrent tumors that arise following therapy in multiple mouse models, and associated with poor survival following recurrence as well as poor overall survival in breast cancer patients. PAQR8 promoted resistance to therapy by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, and treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a Gi protein-dependent reduction in cAMP levels, did not require progesterone, and involved a PAQR8-dependent decrease in ceramide levels and increase in sphingosine-1-phosphate levels, suggesting that PAQR8 may possess ceramidase activity.
CONCLUSIONS: Our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that may commonly contribute to the acquisition of treatment resistance in breast cancer patients.

Keywords: Breast cancer; Endocrine therapy; Translational research; Treatment resistance; Tumor recurrence

DOI: https://doi.org/10.1186/s13058-022-01559-3