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: CCL3

Gene summary for CCL3

Gene summary.

Gene information	Species	Human
	Gene symbol	CCL3
	Gene ID	6348
	Gene name	C-C motif chemokine ligand 3
	Gene Alias	G0S19-1
	Cytomap	17q12
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	A0N0R1

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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
6348	CCL3	C07	Human	Oral cavity	OSCC	1.45e-09	9.85e-01	0.2491
6348	CCL3	C08	Human	Oral cavity	OSCC	5.79e-15	4.90e-01	0.1919
6348	CCL3	C09	Human	Oral cavity	OSCC	2.22e-07	2.39e-01	0.1431
6348	CCL3	LN22	Human	Oral cavity	OSCC	1.98e-02	6.48e-01	0.1733
6348	CCL3	SYSMH2	Human	Oral cavity	OSCC	8.55e-04	2.35e-01	0.2326
6348	CCL3	SYSMH6	Human	Oral cavity	OSCC	1.97e-06	1.99e-01	0.1275
6348	CCL3	P1_S1_AK	Human	Skin	AK	1.79e-02	-1.13e-01	-0.3399
6348	CCL3	P2_S3_AK	Human	Skin	AK	1.79e-02	-1.11e-01	-0.3287
6348	CCL3	P2_S4_SCCIS	Human	Skin	SCCIS	1.79e-02	-1.06e-01	-0.3043
6348	CCL3	cSCC_p1	Human	Skin	cSCC	1.79e-02	-1.13e-01	-0.1916
6348	CCL3	cSCC_p10	Human	Skin	cSCC	1.79e-02	-1.13e-01	-0.2095
6348	CCL3	cSCC_p11	Human	Skin	cSCC	1.79e-02	-1.13e-01	-0.2102
6348	CCL3	cSCC_p4	Human	Skin	cSCC	3.76e-02	-1.12e-01	-0.2022
6348	CCL3	cSCC_p7	Human	Skin	cSCC	3.76e-02	-1.13e-01	-0.2332
6348	CCL3	cSCC_p9	Human	Skin	cSCC	1.79e-02	-1.13e-01	-0.1991
6348	CCL3	PTC05	Human	Thyroid	PTC	3.64e-02	3.51e-01	0.2065
6348	CCL3	PTC06	Human	Thyroid	PTC	3.39e-07	3.71e-01	0.2057
6348	CCL3	PTC07	Human	Thyroid	PTC	1.92e-11	3.41e-01	0.2044
6348	CCL3	ATC09	Human	Thyroid	ATC	1.04e-03	6.85e-01	0.2871
6348	CCL3	ATC1	Human	Thyroid	ATC	1.85e-03	7.52e-01	0.2878

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:001603210	Cervix	CC	viral process	109/2311	415/18723	5.40e-15	6.46e-12	109
GO:002260410	Cervix	CC	regulation of cell morphogenesis	84/2311	309/18723	1.00e-12	4.29e-10	84
GO:00512359	Cervix	CC	maintenance of location	78/2311	327/18723	5.18e-09	4.92e-07	78
GO:00321035	Cervix	CC	positive regulation of response to external stimulus	95/2311	427/18723	5.44e-09	5.03e-07	95
GO:004440310	Cervix	CC	biological process involved in symbiotic interaction	71/2311	290/18723	7.94e-09	6.98e-07	71
GO:00026837	Cervix	CC	negative regulation of immune system process	94/2311	434/18723	2.63e-08	1.87e-06	94
GO:00603267	Cervix	CC	cell chemotaxis	73/2311	310/18723	2.82e-08	1.96e-06	73
GO:00430877	Cervix	CC	regulation of GTPase activity	79/2311	348/18723	4.21e-08	2.60e-06	79
GO:005165110	Cervix	CC	maintenance of location in cell	55/2311	214/18723	6.63e-08	3.85e-06	55
GO:00975298	Cervix	CC	myeloid leukocyte migration	56/2311	220/18723	7.21e-08	4.15e-06	56
GO:003009910	Cervix	CC	myeloid cell differentiation	83/2311	381/18723	1.31e-07	6.42e-06	83
GO:00305957	Cervix	CC	leukocyte chemotaxis	57/2311	230/18723	1.48e-07	7.07e-06	57
GO:190370610	Cervix	CC	regulation of hemopoiesis	80/2311	367/18723	2.14e-07	9.55e-06	80
GO:00716218	Cervix	CC	granulocyte chemotaxis	37/2311	125/18723	2.16e-07	9.56e-06	37
GO:00018197	Cervix	CC	positive regulation of cytokine production	95/2311	467/18723	4.88e-07	1.85e-05	95
GO:00022379	Cervix	CC	response to molecule of bacterial origin	78/2311	363/18723	5.55e-07	2.06e-05	78
GO:00324969	Cervix	CC	response to lipopolysaccharide	74/2311	343/18723	9.15e-07	3.25e-05	74
GO:00509007	Cervix	CC	leukocyte migration	78/2311	369/18723	1.09e-06	3.80e-05	78
GO:00975308	Cervix	CC	granulocyte migration	39/2311	148/18723	2.67e-06	7.87e-05	39
GO:00026857	Cervix	CC	regulation of leukocyte migration	50/2311	210/18723	2.95e-06	8.31e-05	50

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0532314	Cervix	CC	Rheumatoid arthritis	27/1267	93/8465	3.64e-04	1.82e-03	1.07e-03	27
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0516319	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0532315	Cervix	CC	Rheumatoid arthritis	27/1267	93/8465	3.64e-04	1.82e-03	1.07e-03	27
hsa0541745	Cervix	N_HPV	Lipid and atherosclerosis	22/349	215/8465	7.28e-05	7.92e-04	6.19e-04	22
hsa0541755	Cervix	N_HPV	Lipid and atherosclerosis	22/349	215/8465	7.28e-05	7.92e-04	6.19e-04	22
hsa0516312	Liver	Cirrhotic	Human cytomegalovirus infection	87/2530	225/8465	2.67e-03	1.10e-02	6.76e-03	87
hsa0541722	Liver	Cirrhotic	Lipid and atherosclerosis	80/2530	215/8465	1.18e-02	3.81e-02	2.35e-02	80
hsa0532310	Liver	Cirrhotic	Rheumatoid arthritis	38/2530	93/8465	1.52e-02	4.57e-02	2.82e-02	38
hsa0516313	Liver	Cirrhotic	Human cytomegalovirus infection	87/2530	225/8465	2.67e-03	1.10e-02	6.76e-03	87
hsa0541732	Liver	Cirrhotic	Lipid and atherosclerosis	80/2530	215/8465	1.18e-02	3.81e-02	2.35e-02	80
hsa0532311	Liver	Cirrhotic	Rheumatoid arthritis	38/2530	93/8465	1.52e-02	4.57e-02	2.82e-02	38
hsa0516322	Liver	HCC	Human cytomegalovirus infection	131/4020	225/8465	6.86e-04	2.77e-03	1.54e-03	131
hsa05142	Liver	HCC	Chagas disease	61/4020	102/8465	8.04e-03	2.17e-02	1.21e-02	61
hsa0541742	Liver	HCC	Lipid and atherosclerosis	118/4020	215/8465	1.66e-02	3.92e-02	2.18e-02	118
hsa0516332	Liver	HCC	Human cytomegalovirus infection	131/4020	225/8465	6.86e-04	2.77e-03	1.54e-03	131
hsa051421	Liver	HCC	Chagas disease	61/4020	102/8465	8.04e-03	2.17e-02	1.21e-02	61
hsa0541752	Liver	HCC	Lipid and atherosclerosis	118/4020	215/8465	1.66e-02	3.92e-02	2.18e-02	118

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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
CCL3	CCR1	CCL3_CCR1	CCL	Breast	DCIS
CCL3	CCR1	CCL3_CCR1	CCL	Breast	IDC
CCL3	CCR1	CCL3_CCR1	CCL	Cervix	ADJ
CCL3	CCR5	CCL3_CCR5	CCL	Cervix	ADJ
CCL3	CCR1	CCL3_CCR1	CCL	Cervix	CC
CCL3	CCR1	CCL3_CCR1	CCL	Cervix	Healthy
CCL3	CCR1	CCL3_CCR1	CCL	Cervix	Precancer
CCL3	CCR5	CCL3_CCR5	CCL	Endometrium	AEH
CCL3	CCR1	CCL3_CCR1	CCL	Endometrium	Healthy
CCL3	ACKR2	CCL3_ACKR2	CCL	Esophagus	ESCC
CCL3	CCR5	CCL3_CCR5	CCL	HNSCC	ADJ
CCL3	CCR1	CCL3_CCR1	CCL	HNSCC	OSCC
CCL3	ACKR2	CCL3_ACKR2	CCL	HNSCC	OSCC
CCL3	ACKR2	CCL3_ACKR2	CCL	HNSCC	Precancer
CCL3	CCR1	CCL3_CCR1	CCL	Liver	Precancer
CCL3	CCR1	CCL3_CCR1	CCL	Lung	AAH
CCL3	CCR1	CCL3_CCR1	CCL	Lung	ADJ
CCL3	CCR1	CCL3_CCR1	CCL	Lung	AIS
CCL3	CCR1	CCL3_CCR1	CCL	Lung	IAC
CCL3	CCR1	CCL3_CCR1	CCL	Lung	Precancer

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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

CCL3

SNV

Missense_Mutation

novel

c.123N>T

p.Gln41His

p.Q41H

P10147

protein_coding

deleterious(0.01)

benign(0.049)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

CCL3

SNV

Missense_Mutation

novel

c.131N>G

p.Gln44Arg

p.Q44R

P10147

protein_coding

tolerated(1)

benign(0.001)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CCL3

SNV

Missense_Mutation

novel

c.73C>T

p.Leu25Phe

p.L25F

P10147

protein_coding

tolerated(1)

benign(0.005)

TCGA-B5-A3FA-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

CCL3

SNV

Missense_Mutation

novel

c.178C>T

p.Pro60Ser

p.P60S

P10147

protein_coding

deleterious(0.02)

possibly_damaging(0.764)

TCGA-EO-A3AV-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatin

CCL3

SNV

Missense_Mutation

rs773703371

c.203G>A

p.Arg68Gln

p.R68Q

P10147

protein_coding

deleterious(0)

possibly_damaging(0.842)

TCGA-EO-A3AY-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CCL3

SNV

Missense_Mutation

novel

c.232N>A

p.Glu78Lys

p.E78K

P10147

protein_coding

deleterious(0.03)

benign(0.021)

TCGA-DD-A73A-01

Liver

liver hepatocellular carcinoma

Male

>=65

I/II

Unknown

CCL3

SNV

Missense_Mutation

novel

c.273N>A

p.Ser91Arg

p.S91R

P10147

protein_coding

deleterious(0)

benign(0.104)

TCGA-18-3414-01

Lung

lung squamous cell carcinoma

Male

>=65

III/IV

Unknown

CCL3

SNV

Missense_Mutation

rs190805628

c.101G>C

p.Cys34Ser

p.C34S

P10147

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-60-2698-01

Lung

lung squamous cell carcinoma

Male

<65

I/II

Chemotherapy

mithramycin

CCL3

SNV

Missense_Mutation

novel

c.106A>T

p.Ser36Cys

p.S36C

P10147

protein_coding

deleterious(0)

probably_damaging(0.971)

TCGA-85-7843-01

Lung

lung squamous cell carcinoma

Male

<65

I/II

Unknown

CCL3

SNV

Missense_Mutation

rs368462880

c.89N>T

p.Pro30Leu

p.P30L

P10147

protein_coding

deleterious(0.02)

possibly_damaging(0.751)

TCGA-CQ-6229-01

Oral cavity

head & neck squamous cell carcinoma

Male

<65

I/II

Unknown

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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
6348	CCL3	KINASE, DRUGGABLE GENOME		INFLIXIMAB	INFLIXIMAB	16219708
6348	CCL3	KINASE, DRUGGABLE GENOME		Nagrestipen	NAGRESTIPEN
6348	CCL3	KINASE, DRUGGABLE GENOME		ADJUVANT		17116174

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