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Mechanisms of tumor initiation upon disruption of the Rb/E2f interaction

Award Number: R01CA251397
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mechanisms of tumor initiation upon disruption of the Rb/E2f interaction - ABSTRACT E2f (E2f1-8) transcription factors are critical regulators of cell cycle and their activity is physically regulated by Rb family proteins (Rb, p107 and p130). Disruption of the Rb/E2f interaction is a hallmark of cancer, as defined by Hanahan&Weinberg. The acquired resistance to antigrowth signals resulting from this disruption is thought to be necessary for tumor initiation. However, how does unrestricted E2f activity initiates tumorigenesis in vivo is poorly understood and remains a fundamental gap in our understanding of cancer biology. In particular, whether the differentiation status affect the capacity of a cell to transform upon disruption of Rb/E2f interaction is unknown. In addition, whether unrestricted E2f activates other oncogenic features besides aberrant proliferation is still obscure. Hepatocellular carcinoma (HCC) is the second cancer in terms of death worldwide. Limited understanding of the functional consequences for frequent genetic events hampers the development of efficient therapeutics. The Rb/E2f interaction is disrupted in the vast majority of HCC, as a consequence of several events that target upstream components of the Rb/E2f pathway. Therefore, HCC is a relevant model to investigate the consequences of unrestricted E2f activity for cancer initiation. Accordingly, pan-liver inactivation of Rb family genes (Triple Knock Out, TKO) is sufficient to initiate HCC (TKO HCC) that recapitulate multiple features of the human disease. Studies of carcinogen-induced models of HCC have led to the conclusion that hepatocytes are the sole source of HCC. Specific inactivation of Rb family in hepatocytes triggers a short proliferative burst but fails to initiate HCC. This result challenges the current hepato-centric model in the field and suggests that other lineages can also serve as a cell of origin for HCC. Accordingly, inactivation of Rb family in multiple liver lineages reveals that TKO HCC arises from a periductal progenitor. In particular, our preliminary data indicates that unrestricted E2f activity couples aberrant proliferation with cell fate alteration in this population to initiate HCC. Based on these data, we propose to:1) determine the molecular mechanisms that alter the cell fate of a periductal progenitor to serve as a cell of origin for TKO HCC. 2) determine the individual and compound role of E2f factors in TKO HCC initiation and development. 3) determine therapeutic vulnerabilities in TKO HCC that could serve as novel treatment for patients. We believe that our proposal will address fundamental questions regarding the role of E2f in cancer initiation, as identified above. In addition, we expect that our results will establish that different cell lineages can serve as a cell of origin for HCC, which will have important clinical implications, in particular regarding the classification of patients and the development of therapies tailored for different classes of HCC.


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 = $380,395 )
2025	2025	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	6	7/9/2025	NON-COMPETING CONTINUATION	$380,395
														Subtotal = $380,395

Issue Date FY: 2024 ( Subtotal = $361,475 )
2024	2024	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	5	5/24/2024	NON-COMPETING CONTINUATION	$361,475
														Subtotal = $361,475

Issue Date FY: 2023 ( Subtotal = $372,989 )
2023	2023	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	4	6/2/2023	NON-COMPETING CONTINUATION	$372,989
														Subtotal = $372,989

Issue Date FY: 2022 ( Subtotal = $384,512 )
2022	2022	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	004	3	6/24/2022	NON-COMPETING CONTINUATION	$384,512
2022	2021	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	001	2	1/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$309,020
2022	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	1/20/2022	NEW	-$309,020
2022	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	1	2/24/2022	NEW	-$2,193
2022	2021	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	003	2	2/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,193
														Subtotal = $384,512

Issue Date FY: 2021 ( Subtotal = $415,432 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	3/4/2021	NEW	$415,432
														Subtotal = $415,432

Grand Total All Awards = $1,914,803

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Mechanisms of tumor initiation upon disruption of the Rb/E2f interaction

Award Number: R01CA251397

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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