Sang Kyum Kim

Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis

Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.

A basal-like breast cancer-specific role for SRF–IL6 in YAP-induced cancer stemness

The switch between stem/progenitor cell expansion and differentiation is critical for organ homeostasis. The mammalian Hippo pathway effector and oncoprotein YAP expands undifferentiated stem/progenitor cells in various tissues. However, the YAP-associated transcription factors and downstream targets underlying this stemness-promoting activity are poorly understood. Here we show that the SRF–IL6 axis is the critical mediator of YAP-induced stemness in mammary epithelial cells and breast cancer. Specifically, serum response factor (SRF)-mediated binding and recruitment of YAP to mammary stem cell (MaSC) signature-gene promoters induce numerous MaSC signature genes, among which the target interleukin (IL)-6 is critical for YAP-induced stemness. High SRF–YAP/TAZ expression is correlated with IL6-enriched MaSC/basal-like breast cancer (BLBC). Finally, we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer. Collectively, our results establish the importance of SRF–YAP–IL6 signalling in promoting MaSC-like properties in a BLBC-specific manner.

Differential Expression of Enzymes Associated with Serine/Glycine Metabolism in Different Breast Cancer Subtypes

Purpose Glycine and serine are well-known, classic metabolites of glycolysis. Here, we profiled the expression of enzymes associated with serine/glycine metabolism in different molecular subtypes of breast cancer and discuss their potential clinical implications. Methods We used western blotting and immunohistochemistry to examine five serine-/glycine-metabolism–associated proteins (PHGDH, PSAT, PSPH, SHMT, and GLDC) in six breast cancer cell lines and 709 breast cancer cases using tissue microarray (TMA). Results PHGDH and PSPH, associated with serine metabolism, were highly expressed in the TNBC cells. GLDC, associated with glycine metabolism, was highly expressed in HER-2-positive MDA-MB-453 and TNBC-related MDA-MB-435S. TMA showed that the TNBC-type breast cancer tissues highly expressed PHGDH, PSPH, and SHMT1, but not the luminal-A-type tissues (p<0.001). PSPH and SHMT1 expression in the tumor stroma of HER-2-type cancers was the highest, but the luminal-A tissues showed the lowest expression (p<0.001). GLDC was most frequently expressed in cancer cells and stroma of the HER-2-positive cancers and least frequently in TNBC (p<0.001). By Cox multivariate analysis, tumor PSPH positivity (hazard ratio [HR]: 2.068, 95% confidence interval [CI]: 1.049–4.079, p = 0.036), stromal PSPH positivity (HR: 2.152, 95% CI: 1.107–4.184, p = 0.024), and stromal SHMT1 negativity (HR: 2.142, 95% CI: 1.219–3.764, p = 0.008) were associated with short overall survival. Conclusions Expression of serine-metabolism–associated proteins was increased in TNBC and decreased in the luminal-A cancers. Expression of glycine-metabolism–associated proteins was high in the tumor and stroma of HER-2-positive cancers.

Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells.

Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.

Mammalian Sterile 20–like Kinase 1 Suppresses Lymphoma Development by Promoting Faithful Chromosome Segregation

The mammalian Hippo signaling pathway has been implicated in oncogenesis in the context of solid tumors such as hepatocellular carcinoma. Mammalian sterile 20-like kinase 1 (MST1), the core component of the Hippo signaling pathway, is highly expressed in hematopoietic cells. However, its possible impact on tumorigenesis in this setting is unknown. In this study, we provide evidence that Mst1 loss in the mouse enhances chemically and genetically induced lymphoma development by inducing chromosomal instability. Mst1 deficiency increased susceptibility to T-cell acute lymphoblastic leukemia induced by mutagen exposure. Notably, before transformation Mst1(-/-) normal thymocytes showed no changes in proliferation or apoptosis in vitro and in vivo, but they displayed elevated levels of abnormal mitotic chromosomes and aneuploidy, conditions known to promote tumorigenesis. Mst1(-/-) mice also showed accelerated formation of spontaneous lymphomas in a p53-deficient background, accompanied by severe aneuploidy. In clinical specimens of lymphoma and leukemia, we documented frequent downregulation of MST1 expression, consistent with our findings. Taken together, our findings reveal a tumor suppressive function of Mst1 based on its ability to prevent chromosomal instability in lymphocytes.

Differential Features of Pancreatobiliary- and Intestinal-type Ampullary Carcinomas at MR Imaging

PURPOSE To define the differential imaging features of pancreatobiliary- and intestinal-type ampullary carcinomas at magnetic resonance (MR) imaging and to correlate these features with pathologic findings. MATERIALS AND METHODS This retrospective study was approved by the institutional review board; informed consent was waived. Fifty patients with surgically confirmed ampullary carcinoma and preoperative MR results were included. Two radiologists, blinded to histologic type of cancer, evaluated imaging findings in consensus. Univariate and multiple logistic regression analysis were performed to define imaging findings that were useful for differentiation of the two types of carcinomas. RESULTS On the basis of hematoxylin-eosin and immunohistochemical staining, 35 patients were classified as having pancreatobiliary type; and 15 patients, intestinal type. At MR, all of 15 intestinal carcinomas were nodular, whereas 16 (46%) of 35 pancreatobiliary carcinomas were infiltrative. Intestinal carcinomas were isointense (13 [87%] of 15) to hyperintense (two [13%] of 15), whereas 34% (12 of 35) of pancreatobiliary carcinomas manifested as hypointense compared with the duodenum on T2-weighted MR images (P = .034). Intestinal carcinoma commonly manifested with an oval filling defect at the distal end of the bile duct on MR cholangiopancreatographic (MRCP) images (11 [73%] of 15 vs four [11%] of 35 in pancreatobiliary type) (P < .001). At endoscopy, intestinal carcinoma manifested with an extramural protruding mass (n = 15, 100%) with a papillary surface (n = 11, 73%), whereas pancreatobiliary carcinoma manifested with intramural protruding (n = 5, 28%) or ulcerating (n = 1, 6%) gross morphologic features (P = .047) with a nonpapillary surface (n = 17, 94%) (P < .001). Multiple logistic regression analysis showed that an oval filling defect at the distal end of the bile duct was the only independent finding for differentiating intestinal from pancreatobiliary carcinoma (P = .027). CONCLUSION An oval filling defect at the distal end of the bile duct on MRCP images and an extramural protruding appearance with a papillary surface at endoscopy are likely to suggest intestinal ampullary carcinoma.

MRI Findings of Rectal Submucosal Tumors

Rectal submucosal lesions encompass a wide variety of benign and malignant tumors involving the rectum. With optical colonoscopy, any mass-like protrusion covered by normal mucosa, whether the underlying process is intramural or extramural in origin, may be reported as a submucosal lesion. Whereas the assessment of submucosal lesions may be limited with performing optical colonoscopy, cross-sectional imaging such as CT, transrectal ultrasonography and MRI allows the evaluation of perirectal tissues and pelvic organs in addition to the entire thickness of the rectum, and so this is advantageous for the assessment of rectal submucosal tumors. Among these, MRI is the best investigative modality for soft tissue characterization. Therefore, knowledge of the MRI features of rectal submucosal tumors can help achieve accurate preoperative diagnoses and facilitate the appropriate management.

Metaplastic carcinoma show different expression pattern of YAP compared to triple-negative breast cancer.

The purpose of this study is to examine the expression of Yes-associated protein (YAP) in metaplastic carcinoma and compare to those of triple-negative breast carcinoma (TNBC) for investigation of its implication. Tissue microarrays containing 34 cases of metaplastic carcinoma and 175 cases of TNBC were constructed and immunohistochemical staining was used to evaluate expression of the following proteins: YAP and phosphorylated YAP (pYAP). According to immunohistochemical staining results of cytokeratin 5/6, EGFR, claudin 3, claudin 4, claudin 7, E-cadherin, STAT-1, androgen receptor, and GGT-1, metaplastic carcinoma and TNBC were sub-classified into six subtypes: basal-like type, molecular apocrine type, claudin-low type, immune-related type, mixed type, and null type. Comparing the expression of YAP and pYAP in metaplastic carcinoma and TNBC, the expression of nuclear YAP (p = 0.025), cytoplasmic pYAP (p = 0.010), and nuclear pYAP (p = 0.014) in tumor cell was higher in metaplastic carcinoma than TNBC. In metaplastic carcinoma, the nuclear YAP expression in tumor cell was associated with loss of E-cadherin (p = 0.020) and claudin type (p = 0.020), and the stromal YAP expression was associated with claudin 7 positivity (p = 0.003). In conclusion, the YAP expression in metaplastic carcinoma is higher than that in TNBC, representing the association of stemness and epithelial-mesenchymal transition features in metaplastic carcinoma.

Metastatic Breast Cancer From Rhabdomyosarcoma Mimicking Normal Breast Parenchyma on Sonography

Rhabdomyosarcoma is a common childhood malignancy In breast tissue, it is rarely primary and most often metastatic from another site. 1 To our knowledge, there have been few reports detailing sonographic findings of rhabdomyosarcoma in the breast, 2 and the reports that do exist describe various appearances. Here we report a case of metastatic rhabdomyosarcoma in the breast for which the sonographic features were not well differentiated from the normal breast parenchymal structure.

Outcomes of treatment for malignant peripheral nerve sheath tumors: Different clinical features associated with neurofibromatosis type 1

Purpose Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of sarcoma that occur spontaneously or in association with neurofibromatosis type 1 (NF-1). This study aimed to clinically differentiate these types of MPNSTs. Materials and Methods The study reviewed 95 patients diagnosed with and treated for MPNST at Yonsei University Health System, Seoul, Korea over a 27-year period. The clinical characteristics, prognostic factors, and treatment outcomes of sporadic MPNST (sMPNST) and NF-1 associated MPNST (NF-MPNST) cases were compared. Results Patients with NF-MPNST had a significantly lower median age (32 years vs. 45 years for sMPNST, p=0.012), significantly larger median tumor size (8.2 cm vs. 5.0 cm for sMPNST, p < 0.001), and significantly larger numbers of imaging studies and surgeries (p=0.004 and p < 0.001, respectively). The 10-year overall survival (OS) rate of the patients with MPNST was 52±6%. Among the patients with localized MPNST, patients with NF-MPNST had a significantly lower 10-year OS rate (45±11% vs. 60±8% for sMPNST, p=0.046). Univariate analysis revealed the resection margin, pathology grade, and metastasis to be significant factors affecting the OS (p=0.001, p=0.020, and p < 0.001, respectively). Multivariate analysis of the patients with localized MPNST identified R2 resection and G1 as significant prognostic factors for OS. Conclusion NF-MPNST has different clinical features from sMPNST and requires more careful management. Further study will be needed to develop specific management plans for NF-MPNST.