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	CA_HPV_1	Human	Cervix	CC	1.68e-20	7.94e-01	0.0264
6348	CCL3	N_HPV_1	Human	Cervix	N_HPV	4.45e-02	2.97e-01	0.0079
6348	CCL3	N_HPV_2	Human	Cervix	N_HPV	2.23e-13	5.33e-01	-0.0131
6348	CCL3	S43	Human	Liver	Cirrhotic	2.76e-16	-5.56e-01	-0.0187
6348	CCL3	HCC1_Meng	Human	Liver	HCC	6.33e-35	-2.99e-01	0.0246
6348	CCL3	HCC2_Meng	Human	Liver	HCC	4.26e-11	-5.38e-01	0.0107
6348	CCL3	cirrhotic1	Human	Liver	Cirrhotic	7.39e-12	-2.01e-01	0.0202
6348	CCL3	cirrhotic2	Human	Liver	Cirrhotic	1.23e-11	-6.59e-02	0.0201
6348	CCL3	cirrhotic3	Human	Liver	Cirrhotic	2.91e-05	-3.49e-01	0.0215
6348	CCL3	Pt13.c	Human	Liver	HCC	2.33e-04	3.20e-01	0.0076
6348	CCL3	S014	Human	Liver	HCC	1.64e-02	-4.90e-01	0.2254
6348	CCL3	S015	Human	Liver	HCC	9.86e-06	-5.56e-01	0.2375
6348	CCL3	S016	Human	Liver	HCC	2.35e-11	-5.56e-01	0.2243
6348	CCL3	S027	Human	Liver	HCC	4.29e-06	-1.15e-01	0.2446
6348	CCL3	S029	Human	Liver	HCC	1.55e-02	4.05e-01	0.2581
6348	CCL3	C21	Human	Oral cavity	OSCC	7.97e-76	1.92e+00	0.2678
6348	CCL3	C30	Human	Oral cavity	OSCC	4.56e-54	1.80e+00	0.3055
6348	CCL3	C51	Human	Oral cavity	OSCC	2.31e-14	6.48e-01	0.2674
6348	CCL3	C57	Human	Oral cavity	OSCC	2.96e-02	1.30e-01	0.1679
6348	CCL3	C06	Human	Oral cavity	OSCC	2.57e-09	1.08e+00	0.2699

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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:0043523110	Thyroid	PTC	regulation of neuron apoptotic process	102/5968	212/18723	5.45e-07	8.76e-06	102
GO:0001503110	Thyroid	PTC	ossification	176/5968	408/18723	9.26e-07	1.40e-05	176
GO:005185117	Thyroid	PTC	modulation by host of symbiont process	37/5968	60/18723	1.93e-06	2.64e-05	37
GO:0051651113	Thyroid	PTC	maintenance of location in cell	100/5968	214/18723	3.65e-06	4.67e-05	100
GO:0043525112	Thyroid	PTC	positive regulation of neuron apoptotic process	35/5968	58/18723	7.35e-06	8.60e-05	35
GO:004308718	Thyroid	PTC	regulation of GTPase activity	148/5968	348/18723	1.63e-05	1.71e-04	148
GO:0030099113	Thyroid	PTC	myeloid cell differentiation	160/5968	381/18723	1.75e-05	1.82e-04	160
GO:0009636111	Thyroid	PTC	response to toxic substance	115/5968	262/18723	2.70e-05	2.63e-04	115
GO:0001649111	Thyroid	PTC	osteoblast differentiation	102/5968	229/18723	3.66e-05	3.40e-04	102
GO:003582117	Thyroid	PTC	modulation of process of other organism	53/5968	106/18723	7.63e-05	6.54e-04	53
GO:0034612111	Thyroid	PTC	response to tumor necrosis factor	109/5968	253/18723	1.08e-04	8.69e-04	109
GO:0097305113	Thyroid	PTC	response to alcohol	107/5968	253/18723	2.92e-04	2.07e-03	107
GO:0071356111	Thyroid	PTC	cellular response to tumor necrosis factor	96/5968	229/18723	8.24e-04	5.10e-03	96
GO:003210316	Thyroid	PTC	positive regulation of response to external stimulus	167/5968	427/18723	8.31e-04	5.13e-03	167
GO:004206315	Thyroid	PTC	gliogenesis	121/5968	301/18723	1.30e-03	7.41e-03	121
GO:00434918	Thyroid	PTC	protein kinase B signaling	88/5968	211/18723	1.59e-03	8.81e-03	88
GO:005092115	Thyroid	PTC	positive regulation of chemotaxis	62/5968	141/18723	1.67e-03	9.16e-03	62
GO:005170218	Thyroid	PTC	biological process involved in interaction with symbiont	44/5968	94/18723	1.72e-03	9.44e-03	44
GO:004354714	Thyroid	PTC	positive regulation of GTPase activity	103/5968	255/18723	2.38e-03	1.25e-02	103
GO:00439225	Thyroid	PTC	negative regulation by host of viral transcription	10/5968	14/18723	2.77e-03	1.38e-02	10

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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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