Schematic overview of the cellular and molecular mechanisms involved in the cancer progression, including the proposed cellular and molecular mechanisms in cancer cells trajectory. AT1: alveolar type 1 cells; AT2: alveolar type 2 cells; AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma; EMT: epithelial-mesenchymal transition

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	Gene summary
	Malignant transformation analysis
	Malignant transformation related pathway analysis
	Cell-cell communication analysis
	Single-cell gene regulatory network inference analysis
	Somatic mutation of malignant transformation related genes
	Related drugs of malignant transformation related genes

Gene: MARK3

Gene summary for MARK3

Gene summary.

Gene information	Species	Human
	Gene symbol	MARK3
	Gene ID	4140
	Gene name	microtubule affinity regulating kinase 3
	Gene Alias	CTAK1
	Cytomap	14q32.32-q32.33
	Gene Type	protein-coding
	GO ID	GO:0000226
	UniProtAcc	A0A0A0MT23

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Malignant transformation analysis

Identification of the aberrant gene expression in precancerous and cancerous lesions by comparing the gene expression of stem-like cells in diseased tissues with normal stem cells

Malignant transformation involving gene list.

Entrez ID	Symbol	Replicates	Species	Organ	Tissue	Adj P-value	Log2FC	Malignancy
4140	MARK3	CCI_1	Human	Cervix	CC	4.03e-11	1.53e+00	0.528
4140	MARK3	CCI_2	Human	Cervix	CC	7.45e-09	9.77e-01	0.5249
4140	MARK3	CCI_3	Human	Cervix	CC	2.08e-11	1.01e+00	0.516
4140	MARK3	sample3	Human	Cervix	CC	5.12e-11	3.83e-01	0.1387
4140	MARK3	T3	Human	Cervix	CC	2.95e-14	4.49e-01	0.1389
4140	MARK3	HTA11_3410_2000001011	Human	Colorectum	AD	2.72e-02	-2.97e-01	0.0155
4140	MARK3	HTA11_347_2000001011	Human	Colorectum	AD	6.83e-15	5.45e-01	-0.1954
4140	MARK3	HTA11_411_2000001011	Human	Colorectum	SER	1.31e-03	5.85e-01	-0.2602
4140	MARK3	HTA11_1391_2000001011	Human	Colorectum	AD	4.16e-05	4.39e-01	-0.059
4140	MARK3	HTA11_99999965062_69753	Human	Colorectum	MSI-H	9.75e-05	8.18e-01	0.3487
4140	MARK3	HTA11_99999974143_84620	Human	Colorectum	MSS	4.48e-03	-2.98e-01	0.3005
4140	MARK3	A001-C-207	Human	Colorectum	FAP	5.79e-05	-4.13e-01	0.1278
4140	MARK3	A015-C-203	Human	Colorectum	FAP	2.93e-37	-5.07e-01	-0.1294
4140	MARK3	A015-C-204	Human	Colorectum	FAP	4.69e-05	-3.29e-01	-0.0228
4140	MARK3	A014-C-040	Human	Colorectum	FAP	1.80e-06	-6.16e-01	-0.1184
4140	MARK3	A002-C-201	Human	Colorectum	FAP	2.51e-14	-4.08e-01	0.0324
4140	MARK3	A002-C-203	Human	Colorectum	FAP	2.22e-05	-2.00e-01	0.2786
4140	MARK3	A001-C-119	Human	Colorectum	FAP	4.69e-07	-2.68e-01	-0.1557
4140	MARK3	A001-C-108	Human	Colorectum	FAP	5.10e-21	-3.08e-01	-0.0272
4140	MARK3	A002-C-205	Human	Colorectum	FAP	3.34e-24	-4.90e-01	-0.1236

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
Thyroid		ATC: Anaplastic thyroid cancer
		HT: Hashimoto's thyroiditis
		PTC: Papillary thyroid cancer

∗log2FC in expression of this searched gene in stem-like cells from each diseased tissue sample relative to stem-like cells in normal samples in each tissue plotted against the malignancy continuum. Samples are colored based on if they are from different disease stage.

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Malignant transformation related pathway analysis

Find out the enriched GO biological processes and KEGG pathways involved in transition from healthy to precancer to cancer

Figure of enriched GO biological processes.

Tissue	Disease Stage	Enriched GO biological Processes
Colorectum	AD
Colorectum	SER
Colorectum	MSS
Colorectum	MSI-H
Colorectum	FAP

∗Top 15 enriched GO BP terms are showed in the bar plot of each disease state in each tissue. Each row represents a significant GO biological process which is colored according to the -log10(p.adjust).

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Enriched GO biological processes.

GO ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	Count
GO:005109810	Cervix	CC	regulation of binding	80/2311	363/18723	1.32e-07	6.42e-06	80
GO:005109910	Cervix	CC	positive regulation of binding	42/2311	173/18723	1.07e-05	2.33e-04	42
GO:00181057	Cervix	CC	peptidyl-serine phosphorylation	63/2311	315/18723	6.65e-05	9.47e-04	63
GO:00182096	Cervix	CC	peptidyl-serine modification	66/2311	338/18723	9.58e-05	1.25e-03	66
GO:00433939	Cervix	CC	regulation of protein binding	42/2311	196/18723	2.27e-04	2.55e-03	42
GO:00320927	Cervix	CC	positive regulation of protein binding	21/2311	85/18723	1.27e-03	1.01e-02	21
GO:00353294	Cervix	CC	hippo signaling	12/2311	40/18723	2.44e-03	1.71e-02	12
GO:00353301	Cervix	CC	regulation of hippo signaling	7/2311	21/18723	1.04e-02	4.97e-02	7
GO:0051098	Colorectum	AD	regulation of binding	126/3918	363/18723	6.01e-10	4.88e-08	126
GO:0051099	Colorectum	AD	positive regulation of binding	66/3918	173/18723	1.47e-07	6.64e-06	66
GO:0043393	Colorectum	AD	regulation of protein binding	68/3918	196/18723	5.17e-06	1.34e-04	68
GO:0046777	Colorectum	AD	protein autophosphorylation	74/3918	227/18723	2.48e-05	4.76e-04	74
GO:0032092	Colorectum	AD	positive regulation of protein binding	33/3918	85/18723	1.22e-04	1.78e-03	33
GO:0018105	Colorectum	AD	peptidyl-serine phosphorylation	88/3918	315/18723	1.73e-03	1.43e-02	88
GO:0018209	Colorectum	AD	peptidyl-serine modification	92/3918	338/18723	3.19e-03	2.36e-02	92
GO:00510981	Colorectum	SER	regulation of binding	97/2897	363/18723	1.98e-08	1.43e-06	97
GO:00433931	Colorectum	SER	regulation of protein binding	54/2897	196/18723	1.00e-05	3.31e-04	54
GO:00467771	Colorectum	SER	protein autophosphorylation	60/2897	227/18723	1.36e-05	4.25e-04	60
GO:00510991	Colorectum	SER	positive regulation of binding	46/2897	173/18723	1.12e-04	2.34e-03	46
GO:00181051	Colorectum	SER	peptidyl-serine phosphorylation	66/2897	315/18723	5.47e-03	4.06e-02	66

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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Cell-cell communication analysis

Identification of potential cell-cell interactions between two cell types and their ligand-receptor pairs for different disease states

Ligand

Receptor

LRpair

Pathway

Tissue

Disease Stage

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Single-cell gene regulatory network inference analysis

Find out the significant the regulons (TFs) and the target genes of each regulon across cell types for different disease states

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗The dot plots of a searched regulon are shown for all cell subpopulations in each disease state of each tissue based on the regulon specific score inferred using pySCENIC and by calculating the average expression.

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Somatic mutation of malignant transformation related genes

Annotation of somatic variants for genes involved in malignant transformation

Hugo Symbol

Variant Class

Variant Classification

dbSNP RS

HGVSc

HGVSp

HGVSp Short

SWISSPROT

BIOTYPE

SIFT

PolyPhen

Tumor Sample Barcode

Tissue

Histology

Sex

Age

Stage

Therapy Types

Drugs

Outcome

MARK3

SNV

Missense_Mutation

c.800N>A

p.Arg267Lys

p.R267K

protein_coding

deleterious(0.01)

probably_damaging(0.981)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MARK3

SNV

Missense_Mutation

novel

c.718N>C

p.Gly240Arg

p.G240R

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AC-A5EH-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MARK3

SNV

Missense_Mutation

novel

c.1066N>A

p.Glu356Lys

p.E356K

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-AN-A0FV-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MARK3

SNV

Missense_Mutation

c.2013N>G

p.Asp671Glu

p.D671E

protein_coding

tolerated(0.92)

benign(0.045)

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

MARK3

insertion

Frame_Shift_Ins

novel

c.661_662insTGTA

p.Pro221LeufsTer3

p.P221Lfs*3

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

MARK3

insertion

In_Frame_Ins

novel

c.662_663insCTGGCCCTGCCCCATATTATTCTTGTTTTTTGGTTT

p.Pro221_Glu222insTrpProCysProIleLeuPheLeuPhePheGlyPhe

p.P221_E222insWPCPILFLFFGF

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

MARK3

insertion

In_Frame_Ins

novel

c.209_210insTCTCTCATTTCCTTATCTTTGTGTATGCTGTATTGC

p.Val70_Lys71insLeuSerPheProTyrLeuCysValCysCysIleAla

p.V70_K71insLSFPYLCVCCIA

protein_coding

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

MARK3

SNV

Missense_Mutation

novel

c.530N>A

p.Arg177Gln

p.R177Q

protein_coding

deleterious(0)

probably_damaging(0.992)

TCGA-HM-A4S6-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

MARK3

SNV

Missense_Mutation

rs756154872

c.2110N>A

p.Asp704Asn

p.D704N

protein_coding

tolerated(0.11)

possibly_damaging(0.836)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MARK3

SNV

Missense_Mutation

novel

c.479N>C

p.Arg160Thr

p.R160T

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-VS-A9U6-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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Related drugs of malignant transformation related genes

Identification of chemicals and drugs interact with genes involved in malignant transfromation

(DGIdb 4.0)

Entrez ID	Symbol	Category	Interaction Types	Drug Claim Name	Drug Name	PMIDs
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		ALSTERPAULLONE	ALSTERPAULLONE
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		PF-562271	PF-00562271
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		LY-2090314	LY-2090314
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME	inhibitor	249565876
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		CBP-501	CBP-501
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		OSI-632	OSI-632
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		SOTRASTAURIN	SOTRASTAURIN
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		KENPAULLONE	KENPAULLONE
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		GW441756X	GW441756X
4140	MARK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME		TOZASERTIB	TOZASERTIB

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