In Silico Dissection of the Drug Sensitivity of Mesothelioma Cell Lines

Archana Pal

and Vishal Singh Negi

School of Sciences, PP Savani University, Surat, Gujarat 394125, India

PP Savani University, NH 8, GETCO, Kosamba, Dhamdod, Surat, Gujarat 394125, India

Tel: +91 6355720256; Fax: +91-2612577300

Keywords: Pharmacogenomics GDSC, Mesothelioma, Drug sensitivity

Abstract: Malignant mesothelioma is an extremely aggressive cancer of the mesothelial cells. Asbestos exposure and

genetic predisposition are the two most well-established risk factors for mesothelioma occurrence. It has a

high mortality rate with poor prognosis and high chemotherapeutic resistance via unknown mechanisms. In

this study, we used in silico approach for studying the drug sensitivity response of 21 mesothelioma cell

lines from Genomics of Drug Sensitivity in Cancer’ (GDSC) database. We observed that only three cell

lines displayed sensitivity to various drugs. Among these three cell lines, two mesothelioma cell lines

displayed some commonalities in their drug sensitivities as well as their mutation profiles including,

mutation spectrums, the flanking regions of the mutated base, and their respective heatmaps.

1 INTRODUCTION

Malignant mesothelioma (MM) is an

aggressive cancer of the mesothelial cells with poor

prognosis (Zalcman et al. 2016) and ahigh mortality

rate (Carbone et al. 2012).The predicted number of

incidence is alarming; over 20 million people in the

US alone are on the verge of developing MM due to

asbestos exposure(Carbone et al. 2012) and the

global MM incidence and the resulting mortality

rates may be even higher for the developing nations

which happens to use significantly higher amount of

asbestos than the developed countries (Carbone et al.

2019).There have been several attempts to develop

drugs for MM using doxorubicin,

cyclophosphamide, cisplatin, carboplatin,

gemcitabine, pemetrexed, ethyl pyruvate, and

tremelimumab(Samson et al. 1987; Chahinian et al.

1993; Byrne et al. 1999; White et al. 2000; Kindler

et al. 2001; Hughes et al. 2002; Calabrò et al. 2013;

Pellegrini et al. 2017)in the past. However, the

majority of patients die within 24 months of

diagnosis often due to high chemotherapeutic

resistance via unknown mechanisms(Cortes-Dericks

et al. 2010; Mujoomdar et al. 2010; Tajima et al.

2010; Cregan et al. 2016). The effective treatment of

mesothelioma requires a multidimensional approach

such as finding novel targets and finding suitable

biomarkers for the resistant and sensitive cell lines.

In this study, we used in silico approach to dissect

the drug sensitivity of MM cell lines.

1.1 Primary Mesothelial Cell Lines

Primary cultures of mesothelial cells have

been established from rats, rabbits, mice, and

humans. Mesothelial cell lines provide several

advantages for experimental studies: they provide a

large number of cells isolated from a single donor,

cell lines can be isolated from genetically engineered

mice, and primary cell lines limit the number of

animals required for experiments. However, cell

lines have several disadvantages: variability among

donors, variability in culture conditions in different

laboratories, potential phenotypic and genetic

instability, and a limited life span in vitro. Some of

these disadvantages can be overcome by quality

control procedures.

For example, cell lines should not be

passaged indefinitely; frozen stocks should be

maintained and thawed at regular intervals to

prevent phenotypic and genetic instability. As in all

cell culture models, precautions are required to

prevent cross-contamination and contamination with

bacteria or viruses. DNA profiles could be useful to

identify cell lines; for example Manning et al

established initial

genetic profiles for their panel of human

malignant mesothelioma cell lines. All cultures

should be screened for Mycoplasma and other

pathogens (Masters, et al. 2000).

Technical details regarding primary human

mesothelial cell cultures have been summarized by

Pal, A. and Negi, V.

In Silico Dissection of the Drug Sensitivity of Mesothelioma Cell Lines.

DOI: 10.5220/0009512103250332

In Proceedings of the International Conference on Health Informatics and Medical Application Technology (ICHIMAT 2019), pages 325-332

ISBN: 978-989-758-460-2

325

Versnel et al (Versnel,et al. 1994) and Gerwin

(Gerwin, et al. 1994). Briefly, primary human

mesothelial cells require enriched culture media

supplemented with 10% to 20% fetal bovine serum,

exogenous growth factors [usually epidermal growth

factor (EGF)], insulin, transferrin, and

hydrocortisone. Rabbit, mouse, and rat primary

mesothelial cells require similar growth conditions,

with the important exception that growth of rat

pleural mesothelial cells is inhibited by EGF. As

reviewed by Walker et al , there are additional

differences in expression of growth factors and their

receptors between human and rat mesothelial cells.

Differences in growth factor responses have been

described in primary human mesothelial cell cultures

derived from different donors (Lechners, et al.

1989).

Mesothelial cell cultures have been

characterized by morphology, electronmicroscopy,

immunocytochemistry, and cytogenetic). Although

mesothelial cells can form monolayers with

epithelial morphology, this growth pattern can be

altered in vitro as described below.

At the ultrastructural level, mesothelial cells

typically show surface microvilli, abundant

mitochondria, extensive rough endoplasmic

reticulum, perinuclear intermediate filaments,

desmosomes, and tight junctions. Immuno

cytochemistry is useful to confirm expression of

markers specific for mesothelial cells, especially

coexpression of intermediate filaments, keratin, and

vimentin (Mackay, et.al. 1987) and expression of the

Wilms’ tumor suppressor gene, WT1 (Walker, et

al. 1994). These markers are also useful for the

immunohistochemical diagnosis of human malignant

mesotheliomas (Zeng, et al, Ordozen, et al. 2002).

Cytogenetic studies of human mesothelial cell lines

reveal a normal karyotype that may acquire

abnormalities after several passages (Versnel, et al.

1994). One primary murine mesothelial cell line has

been reported that spontaneously acquired a point

mutation in exon 5 of the p53 tumor suppressor

gene. This mutation increased growth rate in vitro;

however, it did not confer tumorigenicity (Cistulli, et

al. 1992).

Primary cell lines provide a valuable model

to study the cell biology and differentiation of

normal mesothelial cells. Primary cultures have also

been used to investigate the toxicologic effects of

asbestos and man-made mineral fibers (Lechner, et

al. 1991).

The mesothelium is derivedembryologically

from the mesoderm. At approximately embryonic

day 7.5 in the mouse, epithelial cells undergo

mesenchymal differentiation to form the mesoderm

cell layer. This morphologic differentiation is

governed by transcription factors snail and slug that

modulate expression of cadherins and cytoskeletal

proteins characteristic of mature mesothelial cells

(Carver, et al. 2001). In response to mechanical

injury, peritoneal dialysis, or chronic inflammation,

mesothelial cells also revert from an epithelial to a

mesenchymal phe- notype. This transdifferentiation

is termed the epithelial-mesenchymal transition and

has been investigated in primary cultures of human

mesothelial cells isolated from reactive peritoneal

effusions or dialysis effluent. In these pathologic

conditions, human mesothelial cells detach from the

mesothelial monolayer and survive in suspension.

When these reactive mesothelial cells are

placed in monolayer culture, they express epithelial

or mesenchymal phenotypes (Carver, at al. 2001)

characterized the expression of cytoskeletal proteins

including actin, vimentin, and several cytokeratins

by mesothelial cells isolated from ascitic fluid.

Modulation of the epithelial phenotype in vitro

depended on culture conditions: serum, EGF, and

hydrocortisone induced a mesenchymal phenotype,

while supplementation with retinoic acid induced an

epithelial phenotype. The epithelial– mesenchymal

transition of reactive human mesothelial cells in

vitro is characterized by reduced expression of some

cell surface proteoglycans (syndecan-4, glypican-1),

the WT1 tumor suppressor gene, and decreased

expression of E cadherin in parellel with expression

of the transcription factor snail. Transdifferentiation

of omental mesothelial cells in vitro was also

induced by mechanical wounding of mesothelial

monolayers or by exposure to the inflammatory

mediators, transforming growth factor-b1 (TGF-b1)

or interleukin-1b (IL-1b) (Carver, at al. 2001).

Mesothelial cells are sensitive target for

transformation by asbestos fibers. The biologic basis

for this increased sensitivity is unknown. Studies

conducted with cell culture models have provided

evidence that the iron-catalyzed generation of

reactive oxygen species is a plausible mechanism for

asbestos carcinogenicity. Reactive oxygen species

have been implicated in asbestos-induced apoptosis,

chromosomal damage, oxidative DNA damage, and

DNA strand breaks (Ollikainen, et al. 1996) in

human and rat pleural mesothelial cells. Variations

in antioxidant defense mechanisms have been

hypothesized to contribute to pulmonary disease

induced by fibers and particulates (Driscoll, et al.

2002). The antioxidant defense pathways of primary

rat pleural mesothelial cells have been characterized

in detail; these cultures have low catalase activity

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and depend primarily on the glutathione pathway for

protection against oxidant stress (Kinnula, et al.

1992). These mechanistic studies suggest that

mesothelial cells are highly susceptible to DNA and

chromosomal damage in response to asbestos

exposure. Mesothelial cells with asbestos-induced

DNA damage that escape apoptosis may be

precursors for the development of malignant

mesothelioma (Broaddus, et al. 1996).

2 METHOD

2.1 Mesothelioma Cell Lines

The list of mesothelioma cell lines and their

respective COSMIC ids were obtained from the

Genomics of Drug Sensitivity in Cancer’ (GDSC)

database.

2.2 Datasets for Drug Response

The GDSC datasets are generated as a result

of various projects and are categorized into two

datasets, GDSC1 and GDSC2. The original dataset

of GDSC was expanded in the form of GDSC1 by

integrating heterogeneous molecular data of 11,289

tumors and 1,001 cell lines and measuring the

response of 1,001 cancer cell lines to 265 anti-cancer

drugs (Iorio et al. 2016) jointly by Wellcome Sanger

Institute and Massachusetts General Hospital

between 2009 and 2015. In contrast, the GDSC2

dataset was generated by Wellcome Sanger Institute

using the improved methods for screening and

assays. Considering that GDSC2 a more reliable

dataset, all our data are obtained from it and not

from GDSC1.

2.3 Chemical Structures of Drugs

The chemical structures of the sensitive drugs

were obtained from the Inxight: Drugs portal of the

National Center for Advancing Translational

Sciences (NCATS).

2.4 Mutation Spectrums

The mutations spectrum of the cell lines were

obtained from the ‘catalogue of somatic mutations in

cancer (COSMIC) portal. The mutation spectrum

plot displays all the substitution nucleotide base pair

changes on the Y-axis and the frequency on X-axis.

It shows the frequency of six substitution classes

(C:G>A:T, C:G>G:C, C:G>T:A, T:A>A:T,

T:A>C:G & T:A>G:C) and indels (which is used for

insertion or deletion of bases in the genome).

2.5 Flanking Regions of Mutated Bases

The flanking sequence for all mutations

referenced to the pyrimidine base (T>X, T>G, T>C,

T>A: C>X, C>T, C>G, C>A) for each cell lines

were obtained from the COSMIC portal available at

Sanger web server. It displays the mutated base at

position 0 together with the frequency for the 10

bases at the upstream and downstream of the

mutated base.

2.6 Genomic Heatmaps of

Mesothelioma Cell Lines

The genomic heatmaps from the cell line

projects were obtained for NCI-H2795, NCI-H513,

and MSTO-211H cell lines. These heatmaps were

constructed from counts of each mutation-type at

each mutation context corrected for the frequency of

each trinucleotide in the coding region of the

reference genome. The plot shows the log-

transformed values of these ratios. The 5′ base to

each mutated base is shown on the vertical axis and

3′ base on the horizontal axis.

3 RESULT

3.1 Mesothelioma Cell Lines in GDSC

The ‘Genomics of Drug Sensitivity in

Cancer’ (GDSC) database allows access to the drug

sensitivity datasets on a large number of 1001 cell

lines of which 990 cells lines have drug response

data available (Supplementary materials S1). Among

1001 cell lines, 21 belong to mesothelioma cancer

type. These cell lines include NCI-H2369, NCI-

H2373, NCI-H2461, NCI-H2591, NCI-H2595, NCI-

H2722, NCI-H2731, NCI-H2795, NCI-H2803, NCI-

H2804, NCI-H2810, NCI-H2818, NCI-H2869, NCI-

H290, NCI-H513, NCI-IST-MES1, NCI-MPP-89,

NCI-MSTO-211H, NCI-H2052, NCI-H2452, and

NCI-H28.

3.2 Drugs Sensitivity Response of

Mesothelioma Cell Lines and Their

Target Pathways

In the GDSC2 dataset majority of

mesothelioma cell lines (17 out of 21) including,

In Silico Dissection of the Drug Sensitivity of Mesothelioma Cell Lines

327

NCI-H2369, NCI-H2373, NCI-H2461, NCI-H2591,

NCI-H2595, NCI-H2722, NCI-H2731, NCI-H2803,

NCI-H2804, NCI-H2810, NCI-H2818, NCI-H2869,

NCI-H290,NCI-IST-MES1, NCI-MPP-89, NCI-

H2052, NCI-H2452, and NCI-H28 exhibited no

sensitivity to any drugs. In contrastonly 3 of the

mesothelioma cell lines including NCI-H2795,NCI-

H513, and MSTO-211Hexhibited sensitivity to

different drugs. The cell line NCI-H2795 was

sensitive to three different drugs PD173074,

AZD4547, and Cediranib (Table 1, Fig. 1).

Figure 1: Drug sensitivity of mesothelioma cell lines NCI-

H2795 (a). The cell line is sensitive to PD173074 (b),

AZD4547, and (c) Cediranib.

Whereas, the other two cell lines NCI-H513, and

MSTO-211H are sensitive to Acetalax, and

PD173074, respectively (Table 1, Fig. 2).

Table 1: Drug sensitivity of mesothelioma cell lines

S.No. Cell Lines

Sensitivity

to Drugs

Targets IC50

1 NCI-H2369 - - -

2 NCI-H2373 - - -

3 NCI-H2461 - - -

4 NCI-H2591 - - -

5 NCI-H2595 - - -

6 NCI-H2722 - - -

7 NCI-H2731 - - -

8 NCI-H2795 PD173074

FGFR1,

FGFR3 0.527311

AZD4547 FGFR1, 0.658974

FGFR2,

FGFR3

Cediranib

VEGFR,

FLT1, FLT2,

FLT3, FLT4,

KIT,

PDGFRB 0.823688

9 NCI-H2803 - - -

10 NCI-H2804 - - -

11 NCI-H2810 - - -

12 NCI-H2818 - - -

13 NCI-H2869 - - -

14 NCI-H290 - - -

15 NCI-H513 Acetalax - 1.084383

16 IST-MES1 - - -

17 MPP-89 - - -

MSTO-

211H PD173074

FGFR1,

FGFR3 2.17617

19 NCI-H2052 - - -

20 NCI-H2452 - - -

21 NCI-H28 - - -

Thecell line NCI-H2795 was found to be

sensitive for three different drugsPD173074,

AZD4547, and Cediranib. The PD173074 is

inhibitory to FGFR1, and FGFR3; AZD4547 inhibits

FGFR1, FGFR2, and FGFR3. The interesting

commonality between the two drugs is that both

inhibitfibroblast growth factor receptors (FGFRs)

thereby inhibiting thesignal transduction pathways,

and, so, the inhibition of tumor cell proliferation and

tumor cell death. Up-regulation of FGFR, which is a

tyrosine kinase receptor, has been reported in many

tumors, and the sensitivity of NCI-H2795 to the

drugs PD173074 and AZD4547 suggests theover-

expression of FGFRs as the major driving force for

mesothelioma. Similarly, drug cediranib is a potent

inhibitor of vascular endothelial growth factor

(VEGF) receptor tyrosine kinases. Considering the

targets of all these three drugs for which NCI-H2795

is sensitive, it is conceivable that the tyrosine kinase

receptors such as FGFRs and VEGF are over-

expressed in mesothelioma and are essential to

tumor cellular proliferation, differentiation and

survival.Like NCI-H2795, the cell line MSTO-

211His also sensitive to the PD173074, the FGFRs

inhibitor. In contrast, the NCI-H513cell line is

sensitive to Acetalax, which is a laxative and its

specific target is largely unknown. However,

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Acetalax has been shown to trigger a cell starvation

response leading to autophagy, mitochondrial

dysfunction, and autocrine TNFα-mediated

apoptosis(Morrison et al. 2013).

Figure 2: Drug sensitivity of mesothelioma cell lines NCI-

H513 and MSTO-211H. (a-b) NCI-H513 is sensitive to

Acetalax. (c-d) MSTO-211H is sensitive to PD173074.

3.2 Mutation Spectrum of Sensitive

Cell Lines

The mutation spectrum of cell lines NCI-

H2795 and MSTO-211H displays some degree of

similarity. In both cases, the frequency of C:G>T:A

substitution is 630 and 871, respectively, which are

highest among all the different substitution classes.

Additionally, the class of the second most frequent

substitution in both the cell line is also the same; the

T:A>C:G substitution in NCI-H2795 and MSTO-

211H is 375 and 415, respectively (Fig. 3a and b). In

contrast to NCI-H2795 and MSTO-211H, the class

of the most frequent substitution in NCI-H513 is

C:G>A:T followed by C:G>T:A, though the number

of total mutations in each substitution class in NCI-

H513 is significantly higher compared to the other

two cell lines (Fig. 3c).

Figure 3: Mutation spectrum of mesothelioma cell

lines NCI-H2795, MSTO-211H, and NCI- H513.

3.3 Flanking Regions of Mutated Base

Apart from the mutation spectrum, the

flanking sequence for all mutations referenced to the

pyrimidine base (T>X, T>G, T>C, T>A: C>X, C>T,

C>G, C>A) for each cell lines were also analyzed to

test if there is any similarity in the cell lines NCI-

H2795 and MSTO-211H. Interestingly, we observed

that thenucleotide frequency of ten bases upstream

and downstream of the T>X and C>X mutations

were maximum for T>C and C>T, respectively for

both NCI-H2795 and MSTO-211H (Fig. 4). As

conceivable, the nucleotide frequency of ten bases

upstream and downstream of the T>X and C>X

mutations were maximum for T>A and C>A for the

cell line NCI-H513 (Fig. 5).

In Silico Dissection of the Drug Sensitivity of Mesothelioma Cell Lines

329

Figure 5: Extended sequence context diagram of

mesothelioma cell line NCI-H513.

The plots shows 21bp sequence context,

combining data from all mutations in a single

sample. The nucleotide frequencies of ten bases

upstream and downstream of the mutated base are

shown normalised to the frequency across the coding

region of the genome.

3.4 Genomic Heatmaps of

Mesothelioma Cell Lines

The deamination of cytosine in a CpG

dinucleotide context (emphasized by 3, 7, 11, and 15

of the mutation class C>T) is one of the common

features of the genomic heatmaps of all the three

mesothelioma cell lines, NCI-H2795, MSTO-211H,

and NCI-H513 (Fig. 6).

The genomic heatmaps of NCI-H2795 and MSTO-

211H were observed to be quite similar to each other

(Fig. 6a and b). The XpCpA and XpCpT

(emphasized by 1, 5, 4 and 12 in Fig. 6a and by 3, 9,

and 14 in Fig. 6b) are rarely mutated in NCI-H2795

and MSTO-211H (Fig. 6a and b). In the mutation

class C>A, the TpCpG (emphasized by 15 of the

mutation class C>A in Fig. 6a) of NCI-H2795 and

the GpCpG (emphasized by 11 of the mutation class

C>A in Fig. 6b) of MSTO-211H are frequently

mutated. Additionally, in the mutation class C>G,

the triplet ApCpG (emphasized by 3 of the mutation

class C>G in Fig. 6a) of NCI-H2795 and the TpCpG

(emphasized by 15 of the mutation class C>G) in

MSTO-211H have frequently mutated bases.

Moreover, the mutation classes T>A and T>G are

rarely mutated in both NCI-H2795 and MSTO-

211H.In contrast to NCI-H2795 and MSTO-211H,

the cell line NCI-H513 exhibited a high frequency of

mutations in C>A and C>G classes (Fig. 6c).

Figure 6: Genomic heatmap of mesothelioma cell

lines NCI-H2795, MSTO-211H, and NCI-H513.

The heatmap shows the frequency of

mutations for all possible triplet bases normalised

against the frequency across the coding genome.

These triplets are composed of the mutated base

together with the 5’ and 3’ bases. There are 96

possible triplets, 16 for each mutation class (C>A,

C>G, C>T, T>A, T>C, and T>G).

5 CONCLUSION

A vast majority of mesothelioma cell lines in

the GDSC database did not display sensitivity to any

of the drugs tested so far. Drug response data shows

that only three cell lines including NCI-H2795, NCI-

H513, and MSTO-211H exhibitedsensitivity to

different drugs. The NCI-H2795 was sensitive to

PD173074, AZD4547, and cediranib, while MSTO-

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211H and NCI-H513 cell lines are sensitive to

PD173074, and acetalax, respectively.

Interestingly, the targets of the

drugsPD173074, AZD4547, and cediranib are

tyrosine kinase receptors such as FGFRs and VEGF

suggesting that the tyrosine kinase receptors in the

two mesothelioma cell lines, NCI-H2795 and

MSTO-211H, are essential to tumor cellular

proliferation, differentiation, and survival. Unlike

NCI-H2795 and MSTO-211H, the NCI-H513 cell

line is sensitive to Acetalax (and resistant to other

drugs), which is a laxative and its specific target is

largely unknown.

It is conceivable that the genomic mutation

profile of the cell lines, NCI-H2795 and MSTO-

211H, which display similarity in their response to

drugs, is likely similar. Therefore, we also looked

into the mutation spectrum, flanking regions of the

mutated bases, and the heatmaps of the substitution

mutations of these cell lines. As expected these

displayed a very similar mutation profile, which is

strikingly different that of the NCI-H513. This

information along with any future study involving

the study of the transcriptomic profile of resistant

and sensitive cell lines could provide us with

suitable biomarkers for drug sensitivity response.

ACKNOWLEDGEMENTS

Vishal Negi and Archana Pal Negi are

thankful to Dr. ParagSanghani (Provost, PP Savani

University) and ShriVallabhbhaiSavani (President,

PP Savani University) for their support and

providing bioinformatics facility to carry out this

study. Vishal Negi is also thankful to the Dr. Saiful

Anwar Matondang and the organizers of the

International Conference on Health Informatics,

Medical and Application Technology (ICHIMAT-

2019) for inviting him as a keynote speaker.

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