TY - JOUR
T1 - Refining the molecular framework for pancreatic cancer with single-cell and spatial technologies
AU - Guo, Jimmy A.
AU - Hoffman, Hannah I.
AU - Weekes, Colin D.
AU - Zheng, Lei
AU - Ting, David T.
AU - Hwang, William L.
N1 - Funding Information:
This work was supported in part by the UCSF Dean’s Yearlong Fellowship (to J.A. Guo), Chinese American Medical Society (to J.A. Guo), American Society for Clinical Oncology/Conquer Cancer Foundation Young Investigator Award (to W.L. Hwang), Hopper-Belmont Foundation Inspiration Award (to W.L. Hwang, and American Cancer Society/Massachusetts General Hospital Institutional Research Grant (to W.L. Hwang). W.L. Hwang is an Andrew L. Warshaw, M.D. Institute for Pancreatic Cancer Research Fellow. D.T. Ting
Funding Information:
D.T. Ting reports personal fees from NanoString Technologies during the conduct of the study, as well as personal fees and other from ROME Therapeutics, other from PanTher Therapeutics and TellBio Inc., personal fees from Pfizer, Foundation Medicine Inc., EMD Millipore Sigma, and Third Rock Ventures, and grants from PureTech Health, Ribon Therapeutics, and ACD-Biotechne outside the submitted
Funding Information:
This work was supported in part by the UCSF Dean?s Yearlong Fellowship (to J.A. Guo), Chinese American Medical Society (to J.A. Guo), American Society for Clinical Oncology/Conquer Cancer Foundation Young Investigator Award (to W.L. Hwang), Hopper-Belmont Foundation Inspiration Award (to W.L. Hwang, and American Cancer Society/Massachusetts General Hospital Institutional Research Grant (to W.L. Hwang). W.L. Hwang is an Andrew L. Warshaw, M.D. Institute for Pancreatic Cancer Research Fellow. D.T. Ting has research funding from the NIH (U01CA228963, R01CA240924, R01CA235412), The Robert L. Fine Cancer Research Foundation, an SU2CNSF-Lustgarten Foundation Pancreatic Cancer Convergence Research Team grant, and a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research grant (grant No. SU2C-AACRDT26?17). Stand Up To Cancer is a division of the Entertainment Industry Foundation. SU2C-AACR-DT26?17 grant is administered by the American Association for Cancer Research, the scientific partner of SU2C.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/15
Y1 - 2021/7/15
N2 - Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. Although this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically degradative tissue, but emerging studies have and will continue to shed light on intratumoral heterogeneity, malignant–stromal interactions, and subtle transcriptional programs previously obscured at the bulk level. In conjunction with insights provided by single-cell/ nucleus dissociative techniques, spatially resolved technologies should also facilitate the contextualization of gene programs and inferred cell–cell interactions within the tumor architecture. Finally, given that patients often receive neoadjuvant chemotherapy and/or chemoradiotherapy even in resectable disease, deciphering the gene programs enriched in or induced by cytotoxic therapy will be crucial for developing insights into complementary treatments aimed at eradicating residual cancer cells. Taken together, single-cell and spatial technologies provide an unprecedented opportunity to refine the foundations laid by prior bulk molecular studies and significantly augment precision oncology efforts in pancreatic cancer.
AB - Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. Although this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically degradative tissue, but emerging studies have and will continue to shed light on intratumoral heterogeneity, malignant–stromal interactions, and subtle transcriptional programs previously obscured at the bulk level. In conjunction with insights provided by single-cell/ nucleus dissociative techniques, spatially resolved technologies should also facilitate the contextualization of gene programs and inferred cell–cell interactions within the tumor architecture. Finally, given that patients often receive neoadjuvant chemotherapy and/or chemoradiotherapy even in resectable disease, deciphering the gene programs enriched in or induced by cytotoxic therapy will be crucial for developing insights into complementary treatments aimed at eradicating residual cancer cells. Taken together, single-cell and spatial technologies provide an unprecedented opportunity to refine the foundations laid by prior bulk molecular studies and significantly augment precision oncology efforts in pancreatic cancer.
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U2 - 10.1158/1078-0432.CCR-20-4712
DO - 10.1158/1078-0432.CCR-20-4712
M3 - Review article
C2 - 33653818
AN - SCOPUS:85110154425
SN - 1078-0432
VL - 27
SP - 3825
EP - 3833
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -