TY - JOUR
T1 - Metabolic Heterogeneity in Patient Tumor-Derived Organoids by Primary Site and Drug Treatment
AU - Sharick, Joe T.
AU - Walsh, Christine M.
AU - Sprackling, Carley M.
AU - Pasch, Cheri A.
AU - Pham, Dan L.
AU - Esbona, Karla
AU - Choudhary, Alka
AU - Garcia-Valera, Rebeca
AU - Burkard, Mark E.
AU - McGregor, Stephanie M.
AU - Matkowskyj, Kristina A.
AU - Parikh, Alexander A.
AU - Meszoely, Ingrid M.
AU - Kelley, Mark C.
AU - Tsai, Susan
AU - Deming, Dustin A.
AU - Skala, Melissa C.
N1 - Funding Information:
We thank the patients that graciously donated tissue to this study. Thank you to the Translational Science BioCore BioBank, the Translation Research Initiatives in Pathology laboratory (TRIP), and the Experimental Pathology Lab (EPL) at the University of Wisconsin Carbone Cancer Center and their staff members for identifying patients, providing surgical specimens, acquiring clinical data, and performing histology services. The BioBank, TRIP lab, and EPL are supported by the UWCCC core grant P30 CA014520, and the TRIP lab was supported by the UW Department of Pathology and Laboratory Medicine. Thank you also to the Medical College of Wisconsin Surgical Oncology Biorepository and Jenny Grewal for obtaining surgical specimens, and to Mohammed Aldakkak for collecting clinical data on the specimens. Thank you to Amani Gillette, Dr. Mohammad Karim, Shujah Rehman, Ava VanDommelen, and Dr. Jeremy Kratz for their time, expertise, and assistance acquiring and analyzing data. Thank you to Dr. Jens Eickhoff for lending his time and expertise. Thank you to Dr. Alex Walsh for invaluable discussion and advice on patient-derived organoid culture and imaging. This manuscript has been released as a pre-print at bioRxiv (74).
Funding Information:
The Skala laboratory was supported by grants from the NSF Graduate Research Fellowship (DGE-1445197; JS), the NSF (CBET-1642287), Stand Up to Cancer (SU2C-AACR-IG-08-16 and SU2C-AACR-PS-18), and the NIH (R01 CA185747, R01 CA205101, R01 CA211082, R21 CA224280, and U01 TR002383). The Deming laboratory was supported by the NIH (R37 CA226526) and the University of Wisconsin Carbone Cancer Center (Support Grant P30 CA014520 and the UWCCC Pancreatic Cancer Taskforce). The Burkard laboratory was supported by the NIH (R01 CA234904). The Medical College of Wisconsin Department of Surgery was supported by the WeCare Fund for Medical Innovation and Research.
Funding Information:
We thank the patients that graciously donated tissue to this study. Thank you to the Translational Science BioCore BioBank, the Translation Research Initiatives in Pathology laboratory (TRIP), and the Experimental Pathology Lab (EPL) at the University of Wisconsin Carbone Cancer Center and their staff members for identifying patients, providing surgical specimens, acquiring clinical data, and performing histology services. The BioBank, TRIP lab, and EPL are supported by the UWCCC core grant P30 CA014520, and the TRIP lab was supported by the UW Department of Pathology and Laboratory Medicine. Thank you also to the Medical College of Wisconsin Surgical Oncology Biorepository and Jenny Grewal for obtaining surgical specimens, and to Mohammed Aldakkak for collecting clinical data on the specimens. Thank you to Amani Gillette, Dr. Mohammad Karim, Shujah Rehman, Ava VanDommelen, and Dr. Jeremy Kratz for their time, expertise, and assistance acquiring and analyzing data. Thank you to Dr. Jens Eickhoff for lending his time and expertise. Thank you to Dr. Alex Walsh for invaluable discussion and advice on patient-derived organoid culture and imaging. This manuscript has been released as a pre-print at bioRxiv (74). Funding. The Skala laboratory was supported by grants from the NSF Graduate Research Fellowship (DGE-1445197; JS), the NSF (CBET-1642287), Stand Up to Cancer (SU2C-AACR-IG-08-16 and SU2C-AACR-PS-18), and the NIH (R01 CA185747, R01 CA205101, R01 CA211082, R21 CA224280, and U01 TR002383). The Deming laboratory was supported by the NIH (R37 CA226526) and the University of Wisconsin Carbone Cancer Center (Support Grant P30 CA014520 and the UWCCC Pancreatic Cancer Taskforce). The Burkard laboratory was supported by the NIH (R01 CA234904). The Medical College of Wisconsin Department of Surgery was supported by the WeCare Fund for Medical Innovation and Research.
Publisher Copyright:
© Copyright © 2020 Sharick, Walsh, Sprackling, Pasch, Pham, Esbona, Choudhary, Garcia-Valera, Burkard, McGregor, Matkowskyj, Parikh, Meszoely, Kelley, Tsai, Deming and Skala.
PY - 2020/5/15
Y1 - 2020/5/15
N2 - New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity was characterized in breast cancer (BC) and pancreatic cancer (PC) patient-derived organoids. Baseline heterogeneity was analyzed for each patient, demonstrating that single-cell techniques, such as OMI, are required to capture the complete picture of heterogeneity present in a sample. Treatment-induced changes in heterogeneity were also analyzed, further demonstrating that these measurements greatly complement current techniques that only gauge average cellular response. Finally, OMI of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response for the first time. Organoids were treated with the same drugs as the patient's prescribed regimen, and OMI measurements of heterogeneity were compared to patient outcome. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual patients, and to develop new effective therapies that address cellular heterogeneity in cancer.
AB - New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity was characterized in breast cancer (BC) and pancreatic cancer (PC) patient-derived organoids. Baseline heterogeneity was analyzed for each patient, demonstrating that single-cell techniques, such as OMI, are required to capture the complete picture of heterogeneity present in a sample. Treatment-induced changes in heterogeneity were also analyzed, further demonstrating that these measurements greatly complement current techniques that only gauge average cellular response. Finally, OMI of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response for the first time. Organoids were treated with the same drugs as the patient's prescribed regimen, and OMI measurements of heterogeneity were compared to patient outcome. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual patients, and to develop new effective therapies that address cellular heterogeneity in cancer.
KW - breast cancer
KW - cellular metabolism
KW - heterogeneity
KW - optical metabolic imaging
KW - organoid
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85085504111&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085504111&partnerID=8YFLogxK
U2 - 10.3389/fonc.2020.00553
DO - 10.3389/fonc.2020.00553
M3 - Article
C2 - 32500020
AN - SCOPUS:85085504111
SN - 2234-943X
VL - 10
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 553
ER -