Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma

Matsumoto, Toshihide; Oda, Yusuke; Hasegawa, Yoshinori; Hashimura, Miki; Oguri, Yasuko; Inoue, Hisako; Yokoi, Ako; Tochimoto, Masataka; Nakagawa, Mayu; Jiang, Zesong; Saegusa, Makoto

doi:10.1016/j.ajpath.2021.06.009

Cited by 14 publications

(33 citation statements)

References 57 publications

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“…Notably, among major genomic ablations, mutations in ALK conferred significant resistance to both olaparib and platinum therapies, suggesting the potential employment of ALK mutation as a predictive biomarker for treatment resistance (Figure 4A). Previous molecular studies have consistently demonstrated that ALK overexpression is closely associated with more aggressive phenotypic states of high‐grade serous carcinomas, 33 further consolidating our findings. To perform a quantitative comparison of genomic alterations and well‐known clinical prognostic factors, we evaluated the hazard ratios using Cox proportional hazard regression model.…”

Section: Resultssupporting

confidence: 87%

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047)

Jason

Kim²,

Kang

et al. 2022

Intl Journal of Cancer

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Through the wide adaptation of next-generation sequencing (NGS) technology within clinical practice, molecular profiling of the tumor has been the principal component of personalized treatment. In our study, we have generated a large collection of cancer genomes on East Asian epithelial ovarian carcinoma (EOC) patients and demonstrate the feasibility and utility of NGS platforms to explore the dynamic interrelations of major cancer driver alterations and their impacts on clinical prognosis and management. A total of 652 EOC patients have undergone clinical NGS panels to determine

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Section: Resultssupporting

confidence: 87%

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047)

Jason

Kim²,

Kang

et al. 2022

Intl Journal of Cancer

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“…ALK receptor activation triggers different intracellular signaling pathways involved in proliferation, survival and metabolism, including JAK/STAT and Ras/ERK [36,45] . Importantly, some studies suggested that ALK acts as a regulator of stemness in several cancers [46–49] . However, our results were certainly unexpected, since this receptor has been overlooked in PDAC.…”

Section: Discussionmentioning

confidence: 99%

ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

Parejo-Alonso

Royo-García

Espiau-Romera

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling drives tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased CSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients.

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“…For immunohistochemical detection of ALK, the ALK iAEP kit (Nichirei Biosciences, Tokyo, Japan) was applied. Lung carcinoma tissues with ALK overexpression due to a gene abnormality were used as positive controls, as described previously [19,20].…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…For example, chromosomal rearrangements in a subset of lymphomas and lung carcinomas give rise to several gene fusions that contain ALK [17,18]. Deregulated expression of full-length ALK has also been observed in some primary solid tumors including ovarian high-grade serous carcinoma and uterine carcinosarcoma [19,20]. Thus, aberrant ALK overexpression is closely associated with tumor development and progression of a variety of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

Anaplastic lymphoma kinase overexpression enhances an aggressive phenotypic characteristics of endometrial carcinoma

Yokoi

Nakamura

Hashimura

et al. 2022

Preprint

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Background Although anaplastic lymphoma kinase (ALK) overexpression is overexpressed in several primary solid tumor types, its role in endometrial carcinoma (Em Ca) remains unclear. Methods We evaluated expression of ALK and its related molecules in clinical samples consisting of 168 Em Ca tissues. We also used Em Ca cell lines to evaluate the functional role of ALK. Results Cytoplasmic ALK immunoreactivity in the absence of chromosomal rearrangement was positively correlated with ALK mRNA expression, and was significantly higher in Grade (G) 3 Em Ca than in G1 or G2 tumors. ALK immunoreactivity was also significantly associated with expression of cancer stem cell (CSC)-related molecules (cytoplasmic CD133, ALDH1, Sox2) and neuroendocrine markers (CD56 and synaptophysin). Although the proliferative index was significantly higher in ALK-positive Em Ca when compared to ALK- negative malignancies, there was no association between ALK expression and other clinicopathological factors in this disease. In Em Ca cell lines, full-length ALK overexpression increased proliferation, decreased susceptibility to apoptosis, enhanced cancer stem cell features, and accelerated cell mobility, whereas these phenotypes were abrogated in ALK-knockdown cells. Finally, tumors with either wild-type ALK or high ALK mRNA expression were associated with a poorer prognosis when compared to Em Ca with either mutant ALK or low ALK mRNA expression. Conclusion Full-length ALK overexpression occurs in a subset of Em Ca, particularly in G3 tumors, and contributes to establishment and maintenance of aggressive phenotypic characteristics through modulation of several biological processes.

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Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma

Cited by 14 publications

References 57 publications

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047)

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047)

ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

Anaplastic lymphoma kinase overexpression enhances an aggressive phenotypic characteristics of endometrial carcinoma

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