研究者詳細 - 西原　広史

論文 - 西原　広史

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Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma.

Nakamura K, Aimono E, Tanishima S, Imai M, Nagatsuma AK, Hayashi H, Yoshimura Y, Nakayama K, Kyo S, Nishihara H

Diagnostics (Basel, Switzerland) 10 （ 4 ） 2020年04月

査読有り, ISSN 2075-4418

Precision medicine, which includes comprehensive genome sequencing, is a potential therapeutic option for treating high-grade serous carcinoma (HGSC). However, HGSC is a heterogeneous tumor at the architectural, cellular, and molecular levels. Intratumoral molecular heterogeneity currently limits the precision of medical strategies based on the gene mutation status. This study was carried out to analyze the presence of 160 cancer-related genetic alterations in three tissue regions with different pathological features in a patient with HGSC. The patient exhibited histological heterogeneous features with different degrees of large atypical cells and desmoplastic reactions. TP53 mutation, ERBB2 and KRAS amplification, and WT1, CDH1, and KDM6A loss were detected as actionable gene alterations. Interestingly, the ERBB2 and KRAS amplification status gradually changed according to the region examined. The difference was consistent with the differences in pathological features. Our results demonstrate the need for sampling of the appropriate tissue region showing progression of pathological features for molecular analysis to solve issues related to tumor heterogeneity prior to developing precision oncology strategies.

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Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology.

Naito Y, Mishima S, Akagi K, Igarashi A, Ikeda M, Okano S, Kato S, Takano T, Tsuchihara K, Terashima K, Nishihara H, Nishiyama H, Hiyama E, Hirasawa A, Hosoi H, Maeda O, Yatabe Y, Okamoto W, Ono S, Kajiyama H, Nagashima F, Hatanaka Y, Miyachi M, Kodera Y, Yoshino T, Taniguchi H

International journal of clinical oncology 25 （ 3 ） 403 - 417 2020年03月

査読有り, ISSN 1341-9625

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

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Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition.

Mishima S, Taniguchi H, Akagi K, Baba E, Fujiwara Y, Hirasawa A, Ikeda M, Maeda O, Muro K, Nishihara H, Nishiyama H, Takano T, Tsuchihara K, Yatabe Y, Kodera Y, Yoshino T

International journal of clinical oncology 25 （ 2 ） 217 - 239 2020年02月

査読有り, ISSN 1341-9625

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

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Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report.

Hongo H, Kosaka T, Aimono E, Nishihara H, Oya M

Diagnostic pathology 15 （ 1 ） 5 - 5 2020年01月

査読有り

BACKGROUND: Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment. CASE PRESENTATION: A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castration-resistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at < 10 ng/mL, and no radiological progression was detected. The patient's formalin-fixed paraffin-embedded tumor biopsy specimen underwent multiple-gene testing by next-generation sequencing, which identified a FANCA homodeletion. No significant germline mutation was observed. CONCLUSIONS: We describe a case of aggressive, castration-resistant prostate cancer with FANCA homodeletion. Genomic analysis of prostate cancer tissue can be useful to determine optimal treatment of such cancers.

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[Required Human and System Resources for Genomic Medicine].

Aimono E, Nishihara H

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 140 （ 5 ） 651 - 655 2020年

査読有り, ISSN 0031-6903

Advances in genomic medicine have enabled the development of precise cancer therapies (precision cancer medicine) through multigene testing. Toward this end, we have developed a novel clinical sequencing system called PleSSision (Pathologist edited, Mitsubishi Space Software supervised clinical sequence system for personalized medicine) that performs amplicon exome sequencing targeting 160 cancer genes. Using this system, we have examined more than 600 cases over 3 years, and have identified druggable gene alteration in approximately 60% of the cases. Performing such clinical sequencing requires management of the sample quality and sequencing by pathologists and laboratory technicians; bioinformatics analysis by biomedical scientists; and patient care by nurses and pharmacists, all based on specific skills and knowledge of genomics. In addition, patients diagnosed with a hereditary cancer syndrome based on clinical sequencing results must receive care from a genetic counselor and a medical doctor with expertise in genetics. Recently, poly(ADP-ribose)polymerase (PARP) inhibitors and immune checkpoint inhibitors have been used in the treatment of patients with hereditary cancer syndromes, so collaboration involving other medical staff, especially genomic pharmacists, is also required. In this session, we provide an overview of cancer genomic medicine and emphasize the role that genomic pharmacists play in cancer precision medicine.

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[Learning from My Experience: Outpatient Care for Cancer Multigene Genomic Testing].

Aimono E, Iguchi A, Mochida K, Imai M, Hayashi H, Nishihara H

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 140 （ 5 ） 667 - 668 2020年

査読有り, ISSN 0031-6903

We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.

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Impaired mitochondrial oxidative phosphorylation capacity in epicardial adipose tissue is associated with decreased concentration of adiponectin and severity of coronary atherosclerosis

Nakajima T., Yokota T., Shingu Y., Yamada A., Iba Y., Ujihira K., Wakasa S., Ooka T., Takada S., Shirakawa R., Katayama T., Furihata T., Fukushima A., Matsuoka R., Nishihara H., Dela F., Nakanishi K., Matsui Y., Kinugawa S.

Scientific Reports （Scientific Reports） 9 （ 1 ） 3535 - 3535 2019年12月

研究論文（学術雑誌）, 共著, 査読有り

© 2019, The Author(s). Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

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A first Japanese case of neuroendocrine prostate cancer accompanied by lung and brain metastasis with somatic and germline BRCA2 mutation

Kosaka T., Hongo H., Aimono E., Matsumoto K., Hayashida T., Mikami S., Nishihara H., Oya M.

Pathology International （Pathology International） 69 （ 12 ） 715 - 720 2019年12月

共著, 査読有り, ISSN 13205463

© 2019 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Germline mutations and copy number changes in DNA damage repair (DDR) genes such as BRCA2 are associated with aggressive forms of prostate cancer (PCa). Although the prevalence of BRCA2 variants in PCa is increasing in Japan, the genomic and biological implications in Japanese patients are unclear. An 81-year-old male presented with prostatic adenocarcinoma with neuroendocrine differentiation accompanied by metastatic lung nodule and brain metastases. Platinum-based doublet chemotherapy combined with etoposide resulted in partial and complete remissions of brain and lung metastases, respectively. Next-generation sequencing of biopsy and peripheral blood samples demonstrated a somatic BRCA2 mutation at c.7008-2A>C and a germline mutation at p.E2877*. The patient's son had been diagnosed with breast cancer 2.5 years ago and was found to have the same germline BRCA2 mutation. BRCA2 mutation increases the risks of aggressive PCa and other cancer types in Japanese males. These forms may be highly responsive to platinum-based chemotherapy.

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Cancer gene profiling explores the possible precision medicine for diffuse-type gastric adenocarcinoma.

Marin Ishikawa, Hideyuki Hayashi, Naoya Sakamoto, Shinya Tanaka, Hiroshi Nishihara

Medical oncology (Northwood, London, England) 37 （ 1 ） 10 - 10 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1357-0560

Diffuse type gastric cancer (DGC), a pathological subtype, is one of the most common malignant solid tumors, and mortality of this tumor is not negligible, especially in early-onset cancer patients. In fact, affirmative personalized treatments based on gene profile have not been established yet. The aim of this study was to provide the possible genotype-matched treatment for DGC through comprehensive examination of genomic variants and analysis of clinicopathological characteristics. We retrospectively studied 23 formalin-fixed, paraffin-embedded samples of patients diagnosed as DGC between January 2003 and December 2015 at the Department of Cancer Pathology, Hokkaido University Graduate School of Medicine. The cases were divided into two groups: early-onset (< 50 years old) and elderly-onset (≥ 50 years old) DGC groups. We performed targeted genomic sequencing using a 163 cancer-related gene panel. The sequencing data were analyzed using an original bioinformatics pipeline called GenomeJack and were clinicopathologically evaluated. Intestinal metaplasia and atrophy were highly observed in the adjacent non-cancerous mucosa in the elderly-onset DGC group compared with those in the early-onset DGC group. The number of somatic variants was significantly higher in the elderly-onset DGC group than in the early-onset DGC group. Fifteen patients (65.2%) harbored at least one genomic alteration of the potential target for genotype-matched treatment. In addition, one patient with hypermutation phenotype was diagnosed as Lynch syndrome due to MLH1 mutation, suggesting the sensitivity for the treatment with immune checkpoint inhibitors. Not only does our study demonstrated the potential utility of the targeted genomic sequencing approach for making informed therapeutic decisions, but it also sheds light on DGC pathogenesis and progression.

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Establishment of permutation for cancer risk estimation in the urothelium based on genome-wide DNA methylation analysis

Tsumura K., Arai E., Tian Y., Shibuya A., Nishihara H., Yotani T., Yamada Y., Takahashi Y., Maeshima A.M., Fujimoto H., Nakagawa T., Kume H., Homma Y., Yoshida T., Kanai Y.

Carcinogenesis （Carcinogenesis） 40 （ 11 ） 1308 - 1319 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01433334

© 2019 The Author(s). Published by Oxford University Press. All rights reserved. The aim of this study was to establish permutation for cancer risk estimation in the urothelium. Twenty-six samples of normal control urothelium obtained from patients without urothelial carcinomas (C), 47 samples of non-cancerous urothelium without noticeable morphological changes obtained from patients with urothelial carcinomas (N), and 46 samples of the corresponding cancerous tissue (T) in the learning cohort and 64 N samples in the validation cohort, i.e. 183 tissue samples in total, were analyzed. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation 450K BeadChip, and DNA methylation levels were verified using pyrosequencing and MassARRAY. Amplicon sequencing was performed using the GeneRead DNAseq Targeted Panels V2. Although N samples rarely showed genetic mutations or copy number alterations, they showed DNA methylation alterations at 2502 CpG sites compared to C samples, and such alterations were inherited by or strengthened in T samples, indicating that DNA methylation alterations may participate in field cancerization in the urothelium. Receiver operating characteristic curve analysis confirmed the feasibility of cancer risk estimation to identify urothelium at the precancerous stage by DNA methylation quantification. Cancer risk estimation permutation was established using a combination of two marker CpG loci on the HOXC4, TENM3 and TLR1 genes (sensitivity and specificity 96-100%). Among them, the diagnostic impact of 10 patterns of permutation was successfully validated in the validation cohort (sensitivity and specificity 94-98%). These data suggest that cancer risk estimation using procedures such as urine tests during health checkups might become applicable for clinical use.

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Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex.

Arai Y, Cwetsch AW, Coppola E, Cipriani S, Nishihara H, Kanki H, Saillour Y, Freret-Hodara B, Dutriaux A, Okada N, Okano H, Dehay C, Nardelli J, Gressens P, Shimogori T, D'Onofrio G, Pierani A

Cell reports 29 （ 3 ） 645 - 658.e5 2019年10月

査読有り

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Broad Heterochromatic Domains Open in Gonocyte Development Prior to De Novo DNA Methylation.

Yamanaka S, Nishihara H, Toh H, Eijy Nagai LA, Hashimoto K, Park SJ, Shibuya A, Suzuki AM, Tanaka Y, Nakai K, Carninci P, Sasaki H, Siomi H

Developmental cell 51 （ 1 ） 21 - 34.e5 2019年10月

査読有り, ISSN 1534-5807

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Japanese Case of Enzalutamide-Resistant Prostate Cancer Harboring a SPOP Mutation With Scattered Allelic Imbalance: Response to Platinum-Based Therapy

Watanabe K., Kosaka T., Aimono E., Hongo H., Mikami S., Nishihara H., Oya M.

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 17 （ 5 ） e897 - e902 2019年10月

共著, 査読有り, ISSN 15587673

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Glomangiopericytoma of the Nasal Cavity with CTNNB1 p.S37C Mutation: A Case Report and Literature Review

Kono M., Bandoh N., Matsuoka R., Goto T., Akahane T., Kato Y., Nakano H., Yamaguchi T., Harabuchi Y., Nishihara H.

Head and Neck Pathology （Head and Neck Pathology） 13 （ 3 ） 298 - 303 2019年09月

共著, 査読有り, ISSN 1936055X

© 2018, The Author(s). Glomangiopericytoma (GPC) is a rare mesenchymal tumor arising from the nasal cavity or paranasal sinuses. GPC was categorized as a borderline and low-malignant-potential tumor by the World Health Organization in 2005 and accounts for less than 0.5% of all sinonasal tumors. We report a case of GPC in a 74-year-old woman with a history of recurrent epistaxis and nasal obstruction. A reddish tumor was seen in the right nasal cavity. Enhanced computed tomography showed a mass lesion occupying the right nasal cavity. The tumor, which originated from the nasal septum in the olfactory fissure area, was resected with 5-mm mucosal margins by endoscopic sinus surgery. Histologic examination revealed a uniform proliferation of oval-to-short spindle-shaped cells beneath the epithelium. Immunohistologic analysis demonstrated the tumor cells were positive for α-smooth muscle actin, β-catenin and Vimentin, and negative for AE1/AE3, Bcl-2, CD34, CD117, Factor VIIIR Ag, S-100 protein, or STAT6. The percentage of Ki-67-positive cells was approximately 5%. Genetic analysis using next-generation sequencing revealed a missense mutation in the CTNNB1 gene (c.110C > G, p.S37C). While other CTNNB1 mutations have been described in GPC; this is the first report of this specific mutation. The mutation was confirmed using Sanger sequencing.

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ヒト膵がん由来膵星状細胞を用いた三次元膵がん線維化モデルの構築ならびに異常ECM改築の機序の解析(Pancreatic stellate cells from human pancreatic cancer show aberrant ECM remodeling in 3D engineered fibrotic tissue)

田中啓祥, 西原広史, 正宗淳, 狩野光伸

日本癌学会総会記事（(一社)日本癌学会） 78回 E - 3005 2019年09月

査読有り, ISSN 0546-0476

バイオバンキングが切り拓く新しいがん研究わが国におけるクリニカルバイオバンクネットワークの構築(Innovative cancer research based on biobanking Clinical biobank network in Japan)

武藤学, 金井雅史, 鶴山竜昭, 松本繁巳, 豊岡伸一, 秋田弘俊, 松原久裕, 西原広史, 末岡榮三朗, 池田貞勝

日本癌学会総会記事（日本癌学会） 78回 S11 - 4 2019年09月

査読有り, ISSN 0546-0476

Effectiveness of a genetic test panel designed for gynecological cancer: an exploratory study

Ida K., Miyamoto T., Higuchi S., Takeuchi H., Yamada S., Ono M., Nishihara H., Shiozawa T.

Medical Oncology （Medical Oncology） 36 （ 7 ） 62 - 62 2019年07月

共著, 査読有り, ISSN 13570560

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. To increase diagnostic efficiency and cost-effectiveness, we performed an exploratory genetic test using a newly designed panel containing 28 actionable and druggable genes, alterations in which are frequently reported in gynecological cancers (TANRE-G, Targeted variants ANalysis RElated to Gynecological cancers). Samples consisted of the formalin-fixed, paraffin-embedded tissue of endometrial (4 cases), cervical (3 cases), and ovarian (4 cases) carcinomas. The sequencing procedure was performed using Ion PGM in our institute with related sequencing kits, and data were analyzed using ClinVar. The present system achieved more than 2500 reads in all tumor samples, and enabled a copy number variation analysis. Results showed that actionable and druggable mutations were detected in 82% (9/11) and 64% (7/11) of cases, respectively, which was similar to other commercially available genetic tests. The amplification of MYC and KRAS was also detected. The analysis cost for each sample was JPY 94,000 (USD 850). These results demonstrate the potential of the TANRE-G panel as an effective tool for examining genetic alterations in gynecological cancers.

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Comprehensive validation of liquid-based cytology specimens for next-generation sequencing in cancer genome analysis

Akahane T., Yamaguchi T., Kato Y., Yokoyama S., Hamada T., Nishida Y., Higashi M., Nishihara H., Suzuki S., Ueno S., Tanimoto A.

PLoS ONE （PLoS ONE） 14 （ 6 ） e0217724 2019年06月

共著, 査読有り

© 2019 Akahane et al. In addition to conventional cytology, liquid-based cytology (LBC) is also used for immunocytochemistry and gene analysis. However, an appropriate method to obtain high quality DNA for next-generation sequencing (NGS) using LBC specimens remains controversial. We determined the optimal conditions for fixation with an alcohol-based fixative for LBC and DNA extraction using cultured cancer cell lines and clinical specimens. The extracted DNA was processed for NGS after the DNA quality was confirmed based on the DNA concentration and degree of degradation. The optimal conditions for cultured cells to obtain high quality DNA were to fix the cells at a density of 6 × 103 or 2 × 104 cells/mL and to use the magnetic bead-based DNA extraction method. Even after storing the fixed cells for 90 days, DNA extracted using the above and other extraction kits, including membrane-based methods, did not undergo degradation. Furthermore, 5-year-old residual LBC samples demonstrated high DNA quality that was suitable for NGS. Furthermore, a cancer genome panel analysis was successfully performed with DNA extracted from cultured cells fixed at 6 × 103 cells/mL for 90 days, and with DNA from residual LBC samples even after 1 year of storage. Residual LBC samples may be a useful source of DNA for clinical NGS to promote genomebased cancer medicine.

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Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status

Fukuda K., Takeuchi S., Arai S., Katayama R., Nanjo S., Tanimoto A., Nishiyama A., Nakagawa T., Taniguchi H., Suzuki T., Yamada T., Nishihara H., Ninomiya H., Ishikawa Y., Baba S., Takeuchi K., Horiike A., Yanagitani N., Nishio M., Yano S.

Cancer Research （Cancer Research） 79 （ 7 ） 1658 - 1670 2019年04月

共著, 査読有り, ISSN 00085472

© 2019 American Association for Cancer Research. Mutations in the ALK gene are detectable in approximately 40% of ALK-rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK-mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK-rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. Significance: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.

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Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness

Tanaka H., Kitahara K., Sasaki N., Nakao N., Sato K., Narita H., Shimoda H., Matsusaki M., Nishihara H., Masamune A., Kano M.

Biomaterials （Biomaterials） 192 355 - 367 2019年02月

共著, 査読有り, ISSN 01429612

© 2018 Elsevier Ltd Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.

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