Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Daniel Cui Zhou; Reyka G. Jayasinghe; Siqi Chen; John M. Herndon; Michael D. Iglesia; Pooja Navale; Michael C. Wendl; Wagma Caravan; Kazuhito Sato; Erik Storrs; Chia Kuei Mo; Jingxian Liu; Austin N. Southard-Smith; Yige Wu; Nataly Naser Al Deen; John M. Baer; Robert S. Fulton; Matthew A. Wyczalkowski; Ruiyang Liu; Catrina C. Fronick; Lucinda A. Fulton; Andrew Shinkle; Lisa Thammavong; Houxiang Zhu; Hua Sun; Liang Bo Wang; Yize Li; Chong Zuo; Joshua F. McMichael; Sherri R. Davies; Elizabeth L. Appelbaum; Keenan J. Robbins; Sara E. Chasnoff; Xiaolu Yang; Ashley N. Reeb; Clara Oh; Mamatha Serasanambati; Preet Lal; Rajees Varghese; Jay R. Mashl; Jennifer Ponce; Nadezhda V. Terekhanova; Lijun Yao; Fang Wang; Lijun Chen; Michael Schnaubelt; Rita Jui Hsien Lu; Julie K. Schwarz; Sidharth V. Puram; Albert H. Kim; Sheng Kwei Song; Kooresh I. Shoghi; Ken S. Lau; Tao Ju; Ken Chen; Deyali Chatterjee; William G. Hawkins; Hui Zhang; Samuel Achilefu; Milan G. Chheda; Stephen T. Oh; William E. Gillanders; Feng Chen; David G. DeNardo; Ryan C. Fields; Li Ding

doi:10.1038/s41588-022-01157-1

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Daniel Cui Zhou, Reyka G. Jayasinghe, Siqi Chen, John M. Herndon, Michael D. Iglesia, Pooja Navale, Michael C. Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia Kuei Mo, Jingxian Liu, Austin N. Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M. Baer, Robert S. Fulton, Matthew A. Wyczalkowski, Ruiyang Liu, Catrina C. FronickLucinda A. Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang Bo Wang, Yize Li, Chong Zuo, Joshua F. McMichael, Sherri R. Davies, Elizabeth L. Appelbaum, Keenan J. Robbins, Sara E. Chasnoff, Xiaolu Yang, Ashley N. Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R. Mashl, Jennifer Ponce, Nadezhda V. Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui Hsien Lu, Julie K. Schwarz, Sidharth V. Puram, Albert H. Kim, Sheng Kwei Song, Kooresh I. Shoghi, Ken S. Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G. Hawkins, Hui Zhang, Samuel Achilefu, Milan G. Chheda, Stephen T. Oh, William E. Gillanders, Feng Chen, David G. DeNardo, Ryan C. Fields, Li Ding

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Abstract

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

Original language	English (US)
Pages (from-to)	1390-1405
Number of pages	16
Journal	Nature genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s41588-022-01157-1
State	Published - Sep 2022
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Cui Zhou, D., Jayasinghe, R. G., Chen, S., Herndon, J. M., Iglesia, M. D., Navale, P., Wendl, M. C., Caravan, W., Sato, K., Storrs, E., Mo, C. K., Liu, J., Southard-Smith, A. N., Wu, Y., Naser Al Deen, N., Baer, J. M., Fulton, R. S., Wyczalkowski, M. A., Liu, R., ... Ding, L. (2022). Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer. Nature genetics, 54(9), 1390-1405. https://doi.org/10.1038/s41588-022-01157-1

Cui Zhou, D, Jayasinghe, RG, Chen, S, Herndon, JM, Iglesia, MD, Navale, P, Wendl, MC, Caravan, W, Sato, K, Storrs, E, Mo, CK, Liu, J, Southard-Smith, AN, Wu, Y, Naser Al Deen, N, Baer, JM, Fulton, RS, Wyczalkowski, MA, Liu, R, Fronick, CC, Fulton, LA, Shinkle, A, Thammavong, L, Zhu, H, Sun, H, Wang, LB, Li, Y, Zuo, C, McMichael, JF, Davies, SR, Appelbaum, EL, Robbins, KJ, Chasnoff, SE, Yang, X, Reeb, AN, Oh, C, Serasanambati, M, Lal, P, Varghese, R, Mashl, JR, Ponce, J, Terekhanova, NV, Yao, L, Wang, F, Chen, L, Schnaubelt, M, Lu, RJH, Schwarz, JK, Puram, SV, Kim, AH, Song, SK, Shoghi, KI, Lau, KS, Ju, T, Chen, K, Chatterjee, D, Hawkins, WG, Zhang, H, Achilefu, S, Chheda, MG, Oh, ST, Gillanders, WE, Chen, F, DeNardo, DG, Fields, RC & Ding, L 2022, 'Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer', Nature genetics, vol. 54, no. 9, pp. 1390-1405. https://doi.org/10.1038/s41588-022-01157-1

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title = "Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer",

abstract = "Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-na{\"i}ve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.",

author = "{Cui Zhou}, Daniel and Jayasinghe, {Reyka G.} and Siqi Chen and Herndon, {John M.} and Iglesia, {Michael D.} and Pooja Navale and Wendl, {Michael C.} and Wagma Caravan and Kazuhito Sato and Erik Storrs and Mo, {Chia Kuei} and Jingxian Liu and Southard-Smith, {Austin N.} and Yige Wu and {Naser Al Deen}, Nataly and Baer, {John M.} and Fulton, {Robert S.} and Wyczalkowski, {Matthew A.} and Ruiyang Liu and Fronick, {Catrina C.} and Fulton, {Lucinda A.} and Andrew Shinkle and Lisa Thammavong and Houxiang Zhu and Hua Sun and Wang, {Liang Bo} and Yize Li and Chong Zuo and McMichael, {Joshua F.} and Davies, {Sherri R.} and Appelbaum, {Elizabeth L.} and Robbins, {Keenan J.} and Chasnoff, {Sara E.} and Xiaolu Yang and Reeb, {Ashley N.} and Clara Oh and Mamatha Serasanambati and Preet Lal and Rajees Varghese and Mashl, {Jay R.} and Jennifer Ponce and Terekhanova, {Nadezhda V.} and Lijun Yao and Fang Wang and Lijun Chen and Michael Schnaubelt and Lu, {Rita Jui Hsien} and Schwarz, {Julie K.} and Puram, {Sidharth V.} and Kim, {Albert H.} and Song, {Sheng Kwei} and Shoghi, {Kooresh I.} and Lau, {Ken S.} and Tao Ju and Ken Chen and Deyali Chatterjee and Hawkins, {William G.} and Hui Zhang and Samuel Achilefu and Chheda, {Milan G.} and Oh, {Stephen T.} and Gillanders, {William E.} and Feng Chen and DeNardo, {David G.} and Fields, {Ryan C.} and Li Ding",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01157-1",

language = "English (US)",

volume = "54",

pages = "1390--1405",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

AU - Cui Zhou, Daniel

AU - Jayasinghe, Reyka G.

AU - Chen, Siqi

AU - Herndon, John M.

AU - Iglesia, Michael D.

AU - Navale, Pooja

AU - Wendl, Michael C.

AU - Caravan, Wagma

AU - Sato, Kazuhito

AU - Storrs, Erik

AU - Mo, Chia Kuei

AU - Liu, Jingxian

AU - Southard-Smith, Austin N.

AU - Wu, Yige

AU - Naser Al Deen, Nataly

AU - Baer, John M.

AU - Fulton, Robert S.

AU - Wyczalkowski, Matthew A.

AU - Liu, Ruiyang

AU - Fronick, Catrina C.

AU - Fulton, Lucinda A.

AU - Shinkle, Andrew

AU - Thammavong, Lisa

AU - Zhu, Houxiang

AU - Sun, Hua

AU - Wang, Liang Bo

AU - Li, Yize

AU - Zuo, Chong

AU - McMichael, Joshua F.

AU - Davies, Sherri R.

AU - Appelbaum, Elizabeth L.

AU - Robbins, Keenan J.

AU - Chasnoff, Sara E.

AU - Yang, Xiaolu

AU - Reeb, Ashley N.

AU - Oh, Clara

AU - Serasanambati, Mamatha

AU - Lal, Preet

AU - Varghese, Rajees

AU - Mashl, Jay R.

AU - Ponce, Jennifer

AU - Terekhanova, Nadezhda V.

AU - Yao, Lijun

AU - Wang, Fang

AU - Chen, Lijun

AU - Schnaubelt, Michael

AU - Lu, Rita Jui Hsien

AU - Schwarz, Julie K.

AU - Puram, Sidharth V.

AU - Kim, Albert H.

AU - Song, Sheng Kwei

AU - Shoghi, Kooresh I.

AU - Lau, Ken S.

AU - Ju, Tao

AU - Chen, Ken

AU - Chatterjee, Deyali

AU - Hawkins, William G.

AU - Zhang, Hui

AU - Achilefu, Samuel

AU - Chheda, Milan G.

AU - Oh, Stephen T.

AU - Gillanders, William E.

AU - Chen, Feng

AU - DeNardo, David G.

AU - Fields, Ryan C.

AU - Ding, Li

PY - 2022/9

Y1 - 2022/9

N2 - Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

AB - Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

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U2 - 10.1038/s41588-022-01157-1

DO - 10.1038/s41588-022-01157-1

M3 - Article

C2 - 35995947

AN - SCOPUS:85136585118

SN - 1061-4036

VL - 54

SP - 1390

EP - 1405

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

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