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: STAT3

Gene summary for STAT3

Gene summary.

Gene information	Species	Human
	Gene symbol	STAT3
	Gene ID	6774
	Gene name	signal transducer and activator of transcription 3
	Gene Alias	ADMIO
	Cytomap	17q21.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P40763

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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
6774	STAT3	CA_HPV_1	Human	Cervix	CC	7.33e-10	-1.83e-01	0.0264
6774	STAT3	N_HPV_1	Human	Cervix	N_HPV	2.41e-02	-9.07e-02	0.0079
6774	STAT3	CCI_2	Human	Cervix	CC	5.81e-10	7.59e-01	0.5249
6774	STAT3	CCII_1	Human	Cervix	CC	4.54e-09	-6.18e-01	0.3249
6774	STAT3	Tumor	Human	Cervix	CC	2.23e-06	-3.55e-01	0.1241
6774	STAT3	sample3	Human	Cervix	CC	1.26e-02	-2.16e-01	0.1387
6774	STAT3	L1	Human	Cervix	CC	3.78e-09	-2.85e-01	0.0802
6774	STAT3	T3	Human	Cervix	CC	3.60e-08	-2.45e-01	0.1389
6774	STAT3	HTA11_1938_2000001011	Human	Colorectum	AD	2.81e-02	4.99e-01	-0.0811
6774	STAT3	HTA11_347_2000001011	Human	Colorectum	AD	2.86e-14	6.84e-01	-0.1954
6774	STAT3	HTA11_696_2000001011	Human	Colorectum	AD	4.43e-06	5.20e-01	-0.1464
6774	STAT3	HTA11_866_2000001011	Human	Colorectum	AD	5.79e-06	5.42e-01	-0.1001
6774	STAT3	HTA11_1391_2000001011	Human	Colorectum	AD	1.50e-12	1.08e+00	-0.059
6774	STAT3	HTA11_866_3004761011	Human	Colorectum	AD	8.85e-10	6.18e-01	0.096
6774	STAT3	HTA11_7696_3000711011	Human	Colorectum	AD	4.40e-02	4.14e-01	0.0674
6774	STAT3	HTA11_99999965104_69814	Human	Colorectum	MSS	3.20e-08	7.39e-01	0.281
6774	STAT3	A015-C-203	Human	Colorectum	FAP	7.21e-24	-3.78e-01	-0.1294
6774	STAT3	A015-C-204	Human	Colorectum	FAP	2.48e-05	-3.51e-01	-0.0228
6774	STAT3	A014-C-040	Human	Colorectum	FAP	4.63e-03	-3.68e-01	-0.1184
6774	STAT3	A002-C-201	Human	Colorectum	FAP	3.09e-08	-7.24e-02	0.0324

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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:00068399	Cervix	CC	mitochondrial transport	60/2311	254/18723	4.21e-07	1.67e-05	60
GO:00018197	Cervix	CC	positive regulation of cytokine production	95/2311	467/18723	4.88e-07	1.85e-05	95
GO:003410110	Cervix	CC	erythrocyte homeostasis	37/2311	129/18723	5.16e-07	1.93e-05	37
GO:00092058	Cervix	CC	purine ribonucleoside triphosphate metabolic process	27/2311	82/18723	9.24e-07	3.25e-05	27
GO:00091458	Cervix	CC	purine nucleoside triphosphate biosynthetic process	24/2311	69/18723	1.21e-06	4.15e-05	24
GO:00091998	Cervix	CC	ribonucleoside triphosphate metabolic process	28/2311	89/18723	1.65e-06	5.44e-05	28
GO:00305229	Cervix	CC	intracellular receptor signaling pathway	60/2311	265/18723	1.89e-06	5.97e-05	60
GO:00067548	Cervix	CC	ATP biosynthetic process	21/2311	57/18723	1.91e-06	5.97e-05	21
GO:003021810	Cervix	CC	erythrocyte differentiation	34/2311	120/18723	2.00e-06	6.18e-05	34
GO:000989510	Cervix	CC	negative regulation of catabolic process	69/2311	320/18723	2.15e-06	6.55e-05	69
GO:004887210	Cervix	CC	homeostasis of number of cells	61/2311	272/18723	2.17e-06	6.55e-05	61
GO:004593610	Cervix	CC	negative regulation of phosphate metabolic process	88/2311	441/18723	2.92e-06	8.27e-05	88
GO:001056310	Cervix	CC	negative regulation of phosphorus metabolic process	88/2311	442/18723	3.21e-06	8.77e-05	88
GO:00092068	Cervix	CC	purine ribonucleoside triphosphate biosynthetic process	23/2311	68/18723	3.47e-06	9.26e-05	23
GO:00616148	Cervix	CC	pri-miRNA transcription by RNA polymerase II	20/2311	55/18723	4.22e-06	1.09e-04	20
GO:00510904	Cervix	CC	regulation of DNA-binding transcription factor activity	87/2311	440/18723	4.85e-06	1.22e-04	87
GO:00092018	Cervix	CC	ribonucleoside triphosphate biosynthetic process	24/2311	74/18723	4.95e-06	1.24e-04	24
GO:00170388	Cervix	CC	protein import	48/2311	206/18723	8.62e-06	1.98e-04	48
GO:00091419	Cervix	CC	nucleoside triphosphate metabolic process	31/2311	112/18723	9.38e-06	2.11e-04	31
GO:004232610	Cervix	CC	negative regulation of phosphorylation	77/2311	385/18723	1.09e-05	2.38e-04	77

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0517120	Cervix	CC	Coronavirus disease - COVID-19	111/1267	232/8465	1.82e-33	5.90e-31	3.49e-31	111
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0520516	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0514514	Cervix	CC	Toxoplasmosis	34/1267	112/8465	2.42e-05	1.82e-04	1.08e-04	34
hsa052128	Cervix	CC	Pancreatic cancer	24/1267	76/8465	1.89e-04	1.11e-03	6.55e-04	24
hsa052234	Cervix	CC	Non-small cell lung cancer	21/1267	72/8465	1.48e-03	6.32e-03	3.74e-03	21
hsa046596	Cervix	CC	Th17 cell differentiation	28/1267	108/8465	1.99e-03	7.98e-03	4.72e-03	28
hsa04062	Cervix	CC	Chemokine signaling pathway	43/1267	192/8465	3.60e-03	1.34e-02	7.91e-03	43
hsa0406618	Cervix	CC	HIF-1 signaling pathway	27/1267	109/8465	4.72e-03	1.64e-02	9.72e-03	27
hsa049336	Cervix	CC	AGE-RAGE signaling pathway in diabetic complications	25/1267	100/8465	5.64e-03	1.88e-02	1.11e-02	25
hsa049172	Cervix	CC	Prolactin signaling pathway	18/1267	70/8465	1.29e-02	3.87e-02	2.29e-02	18
hsa05171110	Cervix	CC	Coronavirus disease - COVID-19	111/1267	232/8465	1.82e-33	5.90e-31	3.49e-31	111
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa05167110	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516319	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0520517	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa05169110	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
STAT3	TREG	Endometrium	ADJ	GNA12,STAT5B,TNFRSF9, etc.	6.57e-02
STAT3	TREG	Endometrium	AEH	GNA12,STAT5B,TNFRSF9, etc.	1.64e-01
STAT3	CD8TEREX	Endometrium	AEH	GNA12,STAT5B,TNFRSF9, etc.	1.21e-01
STAT3	TREG	Endometrium	EEC	GNA12,STAT5B,TNFRSF9, etc.	1.34e-01
STAT3	CD8TEREX	Endometrium	EEC	GNA12,STAT5B,TNFRSF9, etc.	2.12e-01
STAT3	STM	Esophagus	ESCC	ALDH9A1,MALAT1,ETV6, etc.	4.44e-01
STAT3	CD8TEXINT	Lung	ADJ	SLC2A3,CRYBG1,RAPGEF6, etc.	1.13e-01
STAT3	CD8TEXP	Lung	ADJ	SLC2A3,CRYBG1,RAPGEF6, etc.	1.21e-01
STAT3	MDSC	Lung	Healthy	TAPBP,RSPH3,WARS, etc.	8.71e-01
STAT3	MAIT	Oral cavity	NEOLP	HBP1,DPY19L1,VPS37B, etc.	1.89e-01

∗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

STAT3

SNV

Missense_Mutation

novel

c.28C>G

p.Leu10Val

p.L10V

P40763

protein_coding

deleterious(0)

probably_damaging(0.982)

TCGA-A7-A6VX-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

STAT3

SNV

Missense_Mutation

c.2171N>C

p.Leu724Pro

p.L724P

P40763

protein_coding

tolerated(0.13)

possibly_damaging(0.641)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

novel

c.1692N>T

p.Trp564Cys

p.W564C

P40763

protein_coding

deleterious(0.02)

benign(0.015)

TCGA-AC-A8OS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.1229N>G

p.His410Arg

p.H410R

P40763

protein_coding

deleterious(0)

probably_damaging(0.927)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

STAT3

SNV

Missense_Mutation

rs113994137

c.1268N>A

p.Arg423Gln

p.R423Q

P40763

protein_coding

deleterious(0.01)

probably_damaging(0.979)

TCGA-BH-A0B0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

STAT3

SNV

Missense_Mutation

c.1855G>C

p.Val619Leu

p.V619L

P40763

protein_coding

deleterious(0)

benign(0.029)

TCGA-BH-A1F0-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.1151T>A

p.Phe384Tyr

p.F384Y

P40763

protein_coding

deleterious(0.02)

probably_damaging(0.978)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.364N>A

p.Ala122Thr

p.A122T

P40763

protein_coding

tolerated(0.59)

benign(0.006)

TCGA-E9-A1R7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

fareston

STAT3

SNV

Missense_Mutation

c.1907N>T

p.Ser636Phe

p.S636F

P40763

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-GM-A2D9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

STAT3

SNV

Missense_Mutation

novel

c.934C>A

p.Leu312Met

p.L312M

P40763

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-OL-A6VQ-01

Breast

breast invasive carcinoma

Female

<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
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		NICLOSAMIDE	NICLOSAMIDE
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Gold-complexed thiosaccharide derivative 3
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Platinum IV complexe 1
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		GNF-PF-1399	CHEMBL578504
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Salicylic acid derivative 3
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Peptide analog 7
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		CELECOXIB	CELECOXIB	21678971
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		TAK-114
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Salicylic acid derivative 1
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		AZD-1480	AZD-1480	21138246,24978112

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