KEY RESOURCES TABLE

Reagent or resource	Source	Identifier
Biological samples
COLON MAP (Polyp)	See Experimental Model and Subject Details; Data and Code Availability	Synapse: syn23564801 Synapse: syn23630431 Synapse: syn23520239 HTAN Data Portal: HTA11; https://humantumoratlas.org/HTA11
CHTN TMA (CRC)	See Experimental Model and Subject Details; Data and Code Availability	syn21050481: https://doi.org/10.7303/syn21050481
TCPS (Polyp)	See Experimental Model and Subject Details; Data and Code Availability	syn21050481: https://doi.org/10.7303/syn21050481
Critical commercial reagents
Muc2, F-2 clone, A488 dye, antibody	Santa Cruz	Catalog: sc-515032 AF488; RRID: AB_2815005
Collagen Peptide, R-CHP clone, Cy3 dye, antibody	3Helix	Catalog: RED300
SNA, Lectin clone, Cy5 dye, antibody	Vector	Catalog: CL-1305-1
CD11B, C67F154 clone, A488 dye, antibody	Thermo Fisher	Catalog: 53-0196-82; RRID: AB_2637196
CD45, 2D-1 clone, A546 dye, antibody	Santa Cruz	Catalog: sc-1187 AF546; RRID: AB_627073
CD20, D-10 clone, A647 dye, antibody	Santa Cruz	Catalog: sc-393894 AF647
PCNA, PC-10 clone, A488 dye, antibody	Cell Signaling	Catalog: 8580S; RRID: AB_11178664
B-catenin, 12F751 clone, 550 dye, antibody	Vanderbilt Antibody and Protein Resource	Catalog: In-House
p-STAT3, D3A7 clone, A647 dye, antibody	Cell Signaling	Catalog: 4324S; RRID: AB_10694637
pEGFR, EP774Y clone, A488 dye, antibody	Abcam	Catalog: ab205827
CgA, C-12 clone, A546 dye, antibody	Santa Cruz	Catalog: sc-393941; RRID: AB_2801371
CD4, EPR6855 clone, A647 dye, antibody	Abcam	Catalog: ab196147
Cox2, D5H5 clone, A488 dye, antibody	Cell Signaling	Catalog: 13596S; RRID: AB_2798270
CD3d, EP4426 clone, A555 dye, antibody	Abcam	Catalog: ab208514; RRID: AB_2728789
HLA-A, EP1395Y clone, A647 dye, antibody	Abcam	Catalog: ab199837; RRID: AB_2728798
PanCK, AE1/AE3 clone, A488 dye, antibody	Thermo Fisher	Catalog: 53-9003-82; RRID: AB_1834350
OLFM4, D1E4M clone, A555 dye, antibody	Cell Signaling	Catalog: 14369S; RRID: AB_2798465
CD8, C8/114B clone, A647 dye, antibody	Biolegend	Catalog: 372906; RRID: AB_2650712
Alpha-actinin, EPR2533(2) clone, A488 dye, antibody	Abcam	Catalog: ab198608
CD68, KP1 clone, A546 dye, antibody	Santa Cruz	Catalog: sc-20060 AF546; RRID: AB_2891106
NaKATPase, EP1845Y clone, A647 dye, antibody	Abcam	Catalog: ab198367
Vimentin, E-5 clone, A488 dye, antibody	Santa Cruz	Catalog: sc-373717 AF488; RRID: AB_10917747
Sox9, EPR14335 clone, A555 dye, antibody	Abcam	Catalog: ab202516
FOXP3, 206D clone, A647 dye, antibody	Biolegend	Catalog: 320114; RRID: AB_439754
Lysozyme, E-5 clone, A488 dye, antibody	Santa Cruz	Catalog: sc-518012 AF488; RRID: AB_2889359
SMA, 1A4 clone, Cy3 dye, antibody	Millipore Sigma	Catalog: C6198-100UL; RRID: AB_476856
ERBB2, EPR19547 clone, A647 dye, antibody	Abcam	Catalog: ab225510; RRID: AB_2889201
P-p44/42 MAPK, Rabbit Monoclonal antibody	Cell Signaling	Catalog: 4370; RRID: AB_2315112
MUC5AC, Rabbit Monoclonal antibody	Cell Signaling	Catalog: 61193; RRID: AB_2799603
CDX2, Rabbit Monoclonal antibody	Cell Signaling	Catalog: 12306; RRID: AB_2797879
Midkine, Rabbit Monoclonal antibody	Abcam	Catalog: ab52637; RRID: AB_880698
YAP, Rabbit Monoclonal antibody	Cell Signaling	Catalog: 14074; RRID: AB_2650491
MLH1, Rabbit Monoclonal antibody	Abcam	Catalog: Ab92312; RRID: AB_2049968
EPCAM antibody	Santa Cruz	Catalog: Sc-53532; RRID: AB_2277892
GFP antibody	Novus	Catalog: NB600-308SS; RRID: AB_10005904
DCAMKL1 antibody	Abcam	Catalog: ab109029; RRID: AB_10864128
CHGA (C20) antibody	Santa Cruz	Catalog: sc1488; RRID: AB_2276319
MUCIN2 (H-330) antibody	Santa Cruz	Catalog: sc15334; RRID: AB_2146667
CD3 (Sp7) antibody	Thermo Fisher	Catalog: RM-9107-50
CD8 (4SM15) antibody	Invitrogen	Catalog: 14-0808-80; RRID: AB_2572860
CD4 (4SM95) antibody	Invitrogen	Catalog: 14-9766-80; RRID: AB_2573007
CD11b-AF647 antibody	Abcam	Catalog: ab204471; RRID: AB_204471
CD11c antibody	Biolegend	Catalog: 117301; RRID: AB_313770
CD45/B220-AF647 antibody	Biolegend	Catalog: 103228
Hoechst 33342	Invitrogen	Catalog: H3570
Ia/le (M5/114.15.2)	Biolegend	Catalog: 107601
DQ-Ovalbumin	Thermo Fisher	Catalog: D12053
Ovalbumin peptide	Anaspec	Catalog: OVA323-339
CD3-PerCP/Cy5.5, clone 145-2C11	Biolegend	Catalog: 100328; RRID: AB_893318
CD4-Apc-Cy7, clone GK1.5	Biolegend	Catalog: 100414; RRID: AB_312699
MHCII-PE-Cy7, clone M5/144.15.2	Biolegend	Catalog: 107629; RRID: AB_2290801
CD69-FITC, clone H1.2F3	eBioscience	Catalog: 11-0691-82; RRID: AB_465119
CD45-BV785, clone 30-F11	Biolegend	Catalog: 103149; RRID: AB_2564590
Ia/Ie-AF647	Biolegend	Catalog: 10760
ROCK inhibitor	STEMCELL Technologies	Catalog: Y-27632
Matrigel	Corning	Catalog: 356231
RNase A	Thermo Fisher	Catalog: EN0531
Lysing Matrix E	MP Bio	Catalog: 116914100
Mouse Intesticult	STEMCELL Technologies	Catalog: 06005
Gastrin I	Sigma-Aldrich	Catalog: 39024-57-2
TrypLE Express	Thermo Fisher	Catalog: 12604013
N-acetyl-L-cysteine	Sigma-Aldrich	Catalog: A9165
H2O2	Sigma-Aldrich	Catalog: 216763
A83-01	Tocris	Catalog: 2939
IGF-1	Biolegend	Catalog: 590904
FGF-2	Thermo Fisher	Catalog: PHG0024
Primocin	InvivoGen	Catalog: am-pm-05
Human IntestiCult (OGM)	STEMCELL Technologies	Catalog: 06010
Human IntestiCult (ODM)	STEMCELL Technologies	Catalog: 100-0214
Human IFN gamma	Biolegend	Catalog: 570206
CD8-alpha, 53-6.7 clone, antibody	Biolegend	Catalog: 100711; RRID: AB_312750
MHC class I antibody, clone ER-HR 52	Abcam	Catalog: ab15681; RRID: AB_302030
MHC class II (I-A/I-E) antibody, clone (M5/114.15.2)	Thermofisher	Catalog: 14-5321-82; RRID: AB_467561
RT Probe: HLA_A_F	Sigma	AGATACACCTGCCATGTGCAGC
RT Probe: HLA_A_R	Sigma	GATCACAGCTCCAAGGAGAACC
RT Probe: HLA_B_F	Sigma	CTGCTGTGATGTGTAGGAGGAAG
RT Probe: HLA_B_R	Sigma	GCTGTGAGAGACACATCAGAGC
RT Probe: HLA_C_F	Sigma	GGAGACACAGAAGTACAAGCGC
RT Probe: HLA_C_R	Sigma	ACATCCTCTGGAGGGTGTGAGA
RT Probe: CD74_F	Sigma	AAGCCTGTGAGCAAGATGCGCA
RT Probe: CD74_R	Sigma	AGCAGGTGCATCACATGGTCCT
RT Probe: C2TA_F	Sigma	CTACTTCAGGCAGCAGAGGAGA
RT Probe: C2TA_R	Sigma	GCTGTGTCTTCCGAGGAACTTC
RT Probe: HLA-DRB1_F	Sigma	GAGCAAGATGCTGAGTGGAGTC
RT Probe: HLA-DRB1_R	Sigma	CTGTTGGCTGAAGTCCAGAGTG
RT Probe: GAPDH_F	Sigma	GTCTCCTCTGACTTCAACAGCG
RT Probe: GAPDH_R	Sigma	ACCACCCTGTTGCTGTAGCCAA
Deposited data
TCGA (CRC)	(Cancer Genome Atlas Network, 2012)	TCGA GDAC Firehose: COADREAD
SMC (CRC)	(Lee et al., 2020)	GEO: GSE132465
Broad (CRC)	(Pelka et al., 2021)	HTAN Data Portal: HTA1
Software and algorithms
pCreode	(Herring et al., 2018)	https://github.com/Ken-Lau-Lab/pCreode
Scanpy	(Wolf et al., 2018)	https://github.com/theislab/scanpy
Pegasus	Klarman Cell Observatory	https://github.com/klarman-cell-observatory/pegasus
pySCENIC	(Aibar et al., 2017)	https://github.com/aertslab/pySCENIC
CMScaller	(Eide et al., 2017)	https://github.com/peterawe/CMScaller
CytoTRACE	(Gulati et al., 2020)	https://cytotrace.stanford.edu
CMSclassifier	(Guinney et al., 2015)	https://github.com/Sage-Bionetworks/CMSclassifier
Seaborn	Seaborn	https://github.com/mwaskom/seaborn
cBioPortal	(Cerami et al., 2012; Gao et al., 2013)	https://www.cbioportal.org/
Matplotlib	Matplotlib	https://github.com/matplotlib/matplotlib
GATK4	(Poplin et al., 2017)	https://gatk.broadinstitute.org/hc/en-us
DENDRO	(Zhou et al., 2020)	https://github.com/zhouzilu/DENDRO
dropkick	(Heiser et al., 2021)	https://github.com/Ken-Lau-Lab/dropkick
DropEst	(Petukhov et al., 2018)	https://github.com/kharchenkolab/dropEst
STAR	(Dobin et al., 2013)	https://github.com/alexdobin/STAR
Cytoscape	(Shannon et al., 2003)	https://cytoscape.org/
g:Profiler	(Raudvere et al., 2019)	https://biit.cs.ut.ee/gprofiler/
Scipy	(Virtanen et al., 2020)	https://scipy.org/
Sinto	Sinto	https://github.com/timoast/sinto
Dendextend	(Galili, 2015)	https://github.com/talgalili/dendextend
Numpy	(Harris et al., 2020)	https://numpy.org/
Pandas	Pandas	https://pandas.pydata.org/
BWA	(Li and Durbin, 2009)	https://sourceforge.net/projects/maq/
ANNOVAR	(Wang et al., 2010; Yang and Wang, 2015)	https://github.com/WGLab/doc-ANNOVAR
Picard	Broad Institute	https://broadinstitute.github.io/picard/
Sambamba	(Tarasov et al., 2015)	https://github.com/biod/sambamba
lme4	(Bates et al., 2015)	https://github.com/lme4/lme4
lmerTest	(Kuznetsova et al., 2017)	https://github.com/runehaubo/lmerTestR
emmeans	emmeans	https://github.com/rvlenth/emmeans
Cytobank	(Kotecha et al., 2010)	https://www.cytobank.org/
MANDO	(McKinley et al., 2019)	https://github.com/Coffey-Lab/CellSegmentation
UMAP	(McInnes et al., 2018)	https://github.com/lmcinnes/umap
Dask	Dask	https://dask.org/
Harmony	(Korsunsky et al., 2019)	https://github.com/immunogenomics/harmony
Scikit-posthoc	(Terpilowski, 2019)	https://scikit-posthocs.readthedocs.io/en/latest/
GSEA Webapp	(Mootha et al., 2003; Subramanian et al., 2005)	https://www.gsea-msigdb.org/gsea/index.jsp