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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	Tissue samples summary
	Annotation details for different cell compartments
	Cell type statistics by disease state
	Cell type dynamics in malignant transformation
	Cell lineage trajectory inference
	TF regulatory network analysis
	Cell-cell interaction analysis
	Stemness, Senescence, Metaplasia and NeoTCR signature analysis

Tissue: Pancreas

Tissue samples summary

Cell type statistics by tissue samples.

Epithelia	Immune	Stromal
$Bar plot representation of the fraction of all Epithelial cells in each sample composed of each cell type for the integrated scRNA-seq datasets of Breast tissues. Each row represents a single sample, with each color representing a different cell type present in the sample.$	$Bar plot representation of the fraction of all Immune cells in each sample composed of each cell type for the integrated scRNA-seq datasets of Breast tissues. Each row represents a single sample, with each color representing a different cell type present in the sample.$	$Bar plot representation of the fraction of all Stromal cells in each sample composed of each cell type for the integrated scRNA-seq datasets of Breast tissues. Each row represents a single sample, with each color representing a different cell type present in the sample.$

∗Bar plot representation of the fraction of all Epithelial, Immune and Stromal cells in each sample composed of each cell type for the integrated scRNA-seq datasets of Pancreas tissue. Each row represents a single sample, with each color representing a different cell type present in the sample.

Tissue summary table.

Tissue	Disease State	Replicates	Epithelia UMAP	PMID	Source	Platform
Pancreas	PDAC	T1	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T2	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T3	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T4	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T5	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T6	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T7	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T8	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T9	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T10	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T11	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T12	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T13	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T14	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T15	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T16	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T17	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T18	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T19	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics
Pancreas	PDAC	T20	Projection	31273297	https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA001063	10X Genomics

∗Projection of epithelial scRNA-seq cells from Pancreas diseased tissue samples into the manifold of normal tissue epithelial cells. Projected cells are colored by nearest normal cells in the projection and normal epithelial cells are colored gray.

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Annotation details for different cell compartments

Single-cell atlas of expresion.

UMAP representations and annotations of Epithelial cells in the integrated scRNA-seq data of the selected tissue.

UMAP representations and annotations of Immune cells in the integrated scRNA-seq data of the selected tissue.

UMAP representations and annotations of Stromal cells in the integrated scRNA-seq data of the selected tissue.

∗UMAP representations and annotations of Epithelial, Immune, Stromal cells in the integrated scRNA-seq data of Pancreas tissue. Colors represent cell types of each compartment.

Cell markers.

Tissue	Major Cell Type	Minor Cell Type	Full Name	Markers
Pancreas	Epi	DUCT1	Duct-like1 cells	CFTR,BICC1,SLC4A4,GLIS3,SCTR,AMBP,FXYD2,ANXA4,SPP1,SOX9,FOS,JUN
Pancreas	Epi	ACINAR	Acinar cells	SPINK1,CLPS,CPB1,CPA1,PRSS3,PRSS1,AMY2A,AMY2B,CELA2B,CELA3A,CELA3B,SYCN,PNLIP,CTRC,CPA2
Pancreas	Epi	ISLET	Pancreatic islet cells	INS,GCG,SST,GHR,PPY,GCK,PCSK1,PCSK2,CHGA,CHGB,SYP,KCNJ11
Pancreas	Epi	PANIN	PanIN-like cells	MUC5AC,CXCL12,ITGA5,ITGA1,TIMP3,KLF4,IGFBP4,IGFBP7,COL1A1,COL1A2,COL3A1,COL4A1,REG4
Pancreas	Epi	STM	Stem-like cells	EPCAM,CD24,ANPEP,SOX9,CD44,PDX1,ALDH1A1,PROM1,MET
Pancreas	Epi	DUCT2	Duct-like2 cells	CRP,MUC5B,ONECUT2,CRISP3,TFF3
Pancreas	Imm	INMON	Inflamotory monocytes	CD14,CLEC9A,FCGR1A,LILRB2,CD209,CD1E,FCN1,VCAN,S100A8,S100A9
Pancreas	Imm	NEUT	Neutriphils	CEACAM3,FCGR3B,CXCR2
Pancreas	Imm	CD8TEXP	Progenitor exhausted CD8+ T cells	PDCD1,IL7R,GPR183,NR4A3,REL,TCF7
Pancreas	Imm	MAST	Mast cells	TPSAB1,CPA3,HDC,CTSG,TPSB2,CMA1,MS4A2
Pancreas	Imm	CD8TEXINT	Intermediate exhausted CD8+ T cells	PDCD1,LAG3,CD101,CD38,CXCR6,TIGIT
Pancreas	Imm	BN	Naive B cells	CD19,IGHD,IGLL1,CD27,CD38
Pancreas	Imm	CD8TRM	CD8+ tissue resident memory T cells	CD6,XCL1,XCL2,MYADM,CAPG,RORA,NR4A1,NR4A2,NR4A3,CD69,ITGAE
Pancreas	Imm	CD8TEREX	Terminally exhausted CD8+ T cells	TOX,GZMB,ENTPD1,ITGAE,HAVCR2,CXCL13,PDCD1,LAYN,TOX,IFNG,GZMB,MIR155HG,TNFRSF9,ITGAE
Pancreas	Imm	NKT	Natural killer T cells	CD3D,CD3E,NCAM1,KLRB1
Pancreas	Imm	TREG	Regulatory T cells	BATF,TNFRSF4,FOXP3,CTLA4,LAIR2,IL2RA
Pancreas	Imm	CD8TCM	Central memory CD8+ T cells	CCR7,SELL,IL7R,CD27,CD28,PRF1,GZMA,CCL5,GPR183,S1PR1
Pancreas	Imm	MALTB	Mucosa-Associated Lymphoid Tissue B cells	CXCR4,CD80,CCR6,ITGB7
Pancreas	Imm	CD4TN	Naive CD4+ T cells	IL7R,SELL,CCR7,S100A4,TCF7
Pancreas	Imm	CD8TEX	Exhausted CD8+ T cells	PDCD1,LAG3,CD101,CD38,CXCR6,TIGIT
Pancreas	Imm	BMEM	Memory B cells	PAX5,MS4A1,CD19,IGLL5,VPREB3,CD79A,CD79B,IGKC,CD74,HLA-DRA,CD37,CD22
Pancreas	Imm	M1MAC	M1 macrophages	FOLR2,FABP3,PLA2G2D,ITGAM,ITGAX,CSF1R,CD68,CD163,THBD
Pancreas	Imm	PLA	Plasma cells	SSR4,IGLL5,IGLL1,AMPD1,IGHA1,IGHA2,JCHAIN,CD38,TNFRSF17,SDC1,IGHG1,MZB1
Pancreas	Imm	GC	Germinal center B cells	SERPINA9,HRK,HTR3A,BCL6,CD180,FCRLA
Pancreas	Imm	CD8TEFF	Effector CD8+ T cells	CX3CR1,FCGR3A,FGFBP2,PRF1,GZMH,TBX21,EOMES,S1PR1
Pancreas	Imm	GDT	Gamma-delta T cells	TRDC,TRGC1,TRGC2,NKG7,TIGIT
Pancreas	Imm	M2MAC	M2 macrophages	CSF1R,CSF3R,MRC1,IL10,CCL18,VSIG4,CHI3L1
Pancreas	Imm	pDC	Plasmacytoid dendritic cells	IL3RA,CLEC4C,NRP1,KLRD1
Pancreas	Str	MEGA	Megakaryocytes	PF4,VWF,MPL,GP9,GP1BA,GP1BB,CD9,CD36,ITGA2B
Pancreas	Str	SMC	Smooth muscle cells	ACTA2,CNN1,MYH11,TAGLN,CALD1,TAGLN2
Pancreas	Str	PVA	Post capillary venules	SELP,ZNF385D,FAM155A,GALNT15,MADCAM1,CORT
Pancreas	Str	MYOFIB	Myofibroblasts	SYT10,SOSTDC1,DES,TAGLN,MYH11,TPM4
Pancreas	Str	MSC	Mesenchymal stem cells	NT5E,THY1,ENG,CD44,ITGB1,MCAM,ENDOD1
Pancreas	Str	PSC	Pancreatic stellate cells	DES,ACTA2,VIM,NES,PDGFRB,SHH,COL1A1,COL1A2,COL3A1,COL4A1,COL4A2,MMP2,MMP9,MMP13
Pancreas	Str	INCAF	Intermediate cancer-associated fibroblasts	PDGFRA,POSTN,ID1,ID3
Pancreas	Str	ERY	Erythrocytes	HBD,GYPA,HBA1,HBA2,CA1,HBB,BRSK1
Pancreas	Str	CAF	Cancer-associated fibroblasts	TWIST1,WNT2,FAP,CXCL1,CXCL2,CYR61
Pancreas	Str	APCAF	Antigen-presenting cancer-associated fibroblasts	CD74,SAA2,SAA1
Pancreas	Str	FIB	Fibroblasts	BMP7,MAP3K2,COL6A1,CD36,CD44,CBLN2,SPOCK1,ACSS3,FN1,COL3A1,BGN,DCN,POSTN,C1R,MMP2,FGF7,MME,CD47
Pancreas	Str	PERI	Pericytes	PDGFRA,CSPG4,RGS5,MCAM,COX4I2,KCNJ8,HIGD1B,NOTCH3,HEYL,FAM162B
Pancreas	Str	ICAF	Inflammatory cancer-associated fibroblasts	TWIST1,WNT2,FAP,CXCL1,CXCL2,CYR61,IL1B,IL6,HGF
Pancreas	Str	MVA	Microvascular cells	PLVAP,CD36,DYSF,NRP1,SH3BP5,EXOC3L2,FABP5,VWA1,BAALC,PRSS23,RAPGEF4,APLN,HTRA1
Pancreas	Str	LYMEND	Lymphatic endothelial cells	PROX1,LYVE1,PDPN,PROCR,FLT4
Pancreas	Str	ECM	Extracellular matrix	FBLN1,PCOLCE2,MFAP5

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Cell type statistics by disease state

$Stacked bar graph representation of the fraction of each epithelial cell type derived from samples with different Disease States in the integrated dataset of the selected tissue. Cells from each Disease State sample have a different color.$

$Stacked bar graph representation of the fraction of each immune cell type derived from samples with different Disease States in the integrated dataset of the selected tissue. Cells from each Disease State sample have a different color.$

$Stacked bar graph representation of the fraction of each stromal cell type derived from samples with different Disease States in the integrated dataset of the selected tissue. Cells from each Disease State sample have a different color.$

∗Stacked bar graph representation of the fraction of each epithelial cell type derived from samples with different Disease States in the integrated dataset of Pancreas tissue. Cells from each Disease State sample have a different color.

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Cell type dynamics in malignant transformation

∗Fraction of cell type in each scRNA-seq sample plotted against position of the sample in the malignancy continuum for all cell types in Pancreas tissue. Samples are colored based on if they are derived from different Disease States. Cell fractions are computed by dividing the number of cells of a given cell type by the total number of cells in the compartment (epithelial versus immune versus stromal).

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TF regulatory network analysis

Disease State	Epithelia	Immune	Stromal
Healthy
Healthy	TF target network	TF target network	TF target network
ADJ
ADJ	TF target network	TF target network	TF target network
PanIN
PanIN	TF target network	TF target network	TF target network
PDAC
PDAC	TF target network	TF target network	TF target network

∗Heatmap: Heatmap representation of significantly different TFs among all cell types of epithelial compartment in Healthy-derived samples of Pancreas tissue by comparing their average AUC by using pySCENIC in Python. Regulon specific score for each cell type is colored.

∗Network: TF target network created from Healthy-derived samples of Pancreas tissue using Top 50 predicted target genes of each regulon. Edge lengths are the inferred TF-target weightings.

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Stemness, Senescence, Metaplasia and NeoTCR signature analysis

Developmental potential inference using CytoTRACE.

developmental_potential_in_Healthy.png shows the analysis results of stemness, senescence, and metaplasia signatures

developmental_potential_in_PanIN.png shows the analysis results of stemness, senescence, and metaplasia signatures

developmental_potential_in_PDAC.png shows the analysis results of stemness, senescence, and metaplasia signatures

∗Ridge plots of CytoTRACE score distributions for epithelial cells.

Cellular senescence signature (for three compartments).

Disease State	Epithelia	Immune	Stromal
Healthy
PanIN
PDAC

∗Comparisons for degree of cellular senescence among epithelial, immune and stromal cell populations of Pancreas tissue with different disease states.

Metaplasia and damage response signature (for epithelial cells).

Healthy	PanIN	PDAC

∗Comparisons of Metaplasia-associated damage scores among epithelial cell subpopulations.

Neoantigen-specific TCR clonotypes (NeoTCR) signature.

∗Comparisons of CD4+ and CD8+ NeoTCR signature scores among different disease states.