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The role of stem cells and the microenvironment in gastrointestinal cancers

Award Number: R35CA210088
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/07/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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The role of stem cells and the microenvironment in gastrointestinal cancers - SUMMARY/ABSTRACT Timothy C. Wang, NCI R35 Gastrointestinal (GI) cancers most often arise in the setting of chronic inflammation and thus the early evolution of tumors involves extended epithelial interactions with inflammatory stroma. The Wang laboratory has focused for decades on preneoplastic conditions such as gastritis, esophagitis, colitis and pancreatitis, and the impact of stromal changes on epithelial progenitors. Recent work from the lab has characterized the origins of GI cancers from resident stem and progenitor cells, which are expanded during carcinogenesis as a persistent regenerative response, due in part to a shift from asymmetric to symmetric stem cell division. Our lab has used a combination of genetic lineage tracing, 3D organoid models, and single cell RNA-sequencing combined with cutting edge bioinformatic analyses to investigate normal stem and progenitor cells and their early transition to cancer cells. This work has led to a major paradigm shift in our understanding, for example, of the origins of esophageal adenocarcinoma. While the lab has elucidated the role of various stromal cell types, a major focus has been on the role of nerves in modulating both epithelial progenitors as well as other stromal cells. The peripheral nervous system includes sympathetic, parasympathetic, and sensory nerves, and our lab has pioneered the study of these nerves in the development of GI cancers. Recent preliminary data from the laboratory has shown that sensory nerves when activated induce rapid calcium fluxes and modulate the electrical state of tumors cells. In addition, the laboratory has been studying the role of immature myeloid cells (IMC) that in the setting of cancer suppress tumor immunity (i.e., MDSC), and which are also modulated by neural signaling. Previous studies have shown that the trefoil factor TFF2, induced by the inflammatory reflex, modulates IMC and prevents the development and expansion of MDSC which suppress CD8+ T cells in our models. In addition, we have recently been studying the impact of myeloid cells on epigenetic changes in epithelial progenitors. Our work has led to clinical trials and numerous collaborations which we are now seeking to expand, and broaden the impact, particularly in the areas of nerves and cancer. Our proposed studies have the goal of better understanding the crosstalk between nerves, myeloid cells and stem cells that lead to cancer, in order to identify new targets and develop new, more effective and targeted therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $986,058 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	10	8/11/2025	NON-COMPETING CONTINUATION	$986,058
														Subtotal = $986,058

Issue Date FY: 2024 ( Subtotal = $937,650 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	002	9	8/22/2024	NON-COMPETING CONTINUATION	$937,650
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	001	8	2/9/2024	COMPETING CONTINUATION	$943
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	7	2/9/2024	NON-COMPETING CONTINUATION	-$943
														Subtotal = $937,650

Issue Date FY: 2023 ( Subtotal = $1,880,760 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	7	3/16/2023	NON-COMPETING CONTINUATION	$72,960
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	7	11/15/2022	NON-COMPETING CONTINUATION	$820,800
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	003	8	8/11/2023	COMPETING CONTINUATION	$987,000
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	002	7	8/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,880,760

Issue Date FY: 2022 ( Subtotal = $893,760 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	6	11/30/2021	NON-COMPETING CONTINUATION	$820,800
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	6	5/4/2022	NON-COMPETING CONTINUATION	$72,960
														Subtotal = $893,760

Issue Date FY: 2021 ( Subtotal = $871,044 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	5	2/5/2021	NON-COMPETING CONTINUATION	$45,600
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	11/24/2020	NON-COMPETING CONTINUATION	$825,444
														Subtotal = $871,044

Issue Date FY: 2020 ( Subtotal = $860,909 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	4	1/13/2020	NON-COMPETING CONTINUATION	$91,200
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	4	11/21/2019	NON-COMPETING CONTINUATION	$769,709
														Subtotal = $860,909

Issue Date FY: 2019 ( Subtotal = $884,640 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	11/29/2018	NON-COMPETING CONTINUATION	$884,640
														Subtotal = $884,640

Issue Date FY: 2018 ( Subtotal = $912,000 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	2	5/23/2018	NON-COMPETING CONTINUATION	$91,200
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	2	11/21/2017	NON-COMPETING CONTINUATION	$820,800
														Subtotal = $912,000

Issue Date FY: 2017 ( Subtotal = $942,000 )
2017	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	12/7/2016	NEW	$942,000
														Subtotal = $942,000

Grand Total All Awards = $9,168,821

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The role of stem cells and the microenvironment in gastrointestinal cancers

Award Number: R35CA210088

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/07/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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