Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

Changes in nuclear shape have been extensively associated with the dynamics and functionality of cancer cells. In most normal cells, nuclei have a regular ellipsoid shape and minimal variation in nuclear size; however, an irregular nuclear contour and abnormal nuclear size is often observed in cancer, including pancreatic cancer. Furthermore, alterations in nuclear morphology have become the ‘gold standard’ for tumor staging and grading. Beyond the utility of altered nuclear morphology as a diagnostic tool in cancer, the implications of altered nuclear structure for the biology and behavior of cancer cells are profound as changes in nuclear morphology could impact cellular responses to physical strain, adaptation during migration, chromatin organization, and gene expression. Here, we aim to highlight and discuss the factors that regulate nuclear dynamics and their implications for pancreatic cancer biology.

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Breaking the scale: how disrupting the karyoplasmic ratio gives cancer cells an advantage for metastatic invasion

Biochemical Society Transactions ◽

10.1042/bst20170153 ◽

2017 ◽

Vol 45 (6) ◽

pp. 1333-1344

Author(s):

Andrea Rizzotto ◽

Eric C. Schirmer

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Cancer Cells ◽

Nuclear Size ◽

Nuclear Morphology ◽

Metastatic Tumors ◽

Size Regulation ◽

Diagnosis And Prognosis ◽

Ploidy Changes ◽

Tumor Types

Nuclear size normally scales with the size of the cell, but in cancer this ‘karyoplasmic ratio’ is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types.

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MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo

Stem Cells International ◽

10.1155/2019/8475389 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Karolin Walter ◽

Kanishka Tiwary ◽

Marija Trajkovic-Arsic ◽

Ana Hidalgo-Sastre ◽

Laura Dierichs ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Biology ◽

Mesenchymal Transition ◽

Ras Mutations ◽

Mek Inhibition ◽

Pancreatic Cancers ◽

Pancreatic Cancer Cells ◽

Genetically Engineered Mouse Model

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.

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Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells

PLoS ONE ◽

10.1371/journal.pone.0252917 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252917

Author(s):

Tomotaka Kato ◽

Hiroaki Ono ◽

Mikiya Fujii ◽

Keiichi Akahoshi ◽

Toshiro Ogura ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Overall Survival ◽

Drug Resistance ◽

Cancer Cells ◽

Cancer Biology ◽

Disease Free Survival ◽

Acute Response ◽

Pancreatic Cancer Cells

Background RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined. Methods To determine relationships between RRM1 expression and the prognosis of pancreatic cancer, and to explore RRM1 function in cancer biology, we investigated RRM1 expression levels in 121 pancreatic cancer patients by immunohistochemical staining and performed in vitro experiments to analyze the functional consequences of RRM1 expression. Results Patients with high RRM1 expression had significantly poorer clinical outcomes (overall survival; p = 0.006, disease-free survival; p = 0.0491). In particular, high RRM1 expression was also associated with poorer overall survival on adjuvant chemotherapy (p = 0.008). We found that RRM1 expression was increased 24 hours after exposure to gemcitabine and could be suppressed by histone acetyltransferase inhibition. RRM1 activation in response to gemcitabine exposure was induced mainly in the cytoplasm and cytoplasmic RRM1 activation was related to cancer cell viability. In contrast, cancer cells lacking cytoplasmic RRM1 activation were confirmed to show severe DNA damage. RRM1 inhibition with specific siRNA or hydroxyurea enhanced the cytotoxic effects of gemcitabine for pancreatic cancer cells. Conclusions Cytoplasmic RRM1 activation is involved in biological processes related to drug resistance in response to gemcitabine exposure and could be a potential target for pancreatic cancer treatment.

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