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Cancer under pressure: Mechanisms of adaptation to compressive stress

Award Number: R37CA240765
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Cancer under pressure: Mechanisms of adaptation to compressive stress - SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a one-year survival rate of only 20%. A major barrier to treatment is that activating mutations in KRAS (e.g. KRASG12D) drive >90% of PDAC, but there are currently no effective drugs that target this classic oncogene. PDAC is also characterized by the build- up of more compressive stress than any other tumor. The effects of mechanical compressive stress are also poorly understood. Compressive stress distorts and compresses cells leading to increased intracellular molecular crowding. This crowding has two key effects: molecular motion is inhibited, and also molecular assembly is increased as molecules are pushed together. We have found that increased molecular crowding greatly favors phase separation, and drives stress granule formation. Our original hypothesis was that KRASG12D oncogene activation would confer resistance to mechanical compression. In fact, the opposite was true: KRASG12D softens cells, leading to increased susceptibility to compressive stress. The consequent high molecular crowding increased stress granules, which we found actually help alleviate molecular crowding by sequestering RNA. We are now determining if stress granules are key for survival under compressive stress. High crowding and distortion also led to imbalances in the physical properties of mitotic spindles, issues with DNA replication, and frequent nuclear ruptures, all of which contribute to an extremely high rate of mitotic errors when KRASG12D and compression are combined. We therefore, investigated the new hypothesis that the combination of KRAS mutation and compression accelerate cancer cell evolution. In support of this idea, we found frequent and highly stereotyped aneuploidies in cells that we evolved in vitro under compression for one month. We also saw frequent whole genome duplications and mutation of TP53. The evolved cells were able to outcompete parent cells when grown under mechanical compression, indicating that they had adapted to this perturbed mechanical environment. We will now determine the mechanisms of this adaptation. We also identified Myc in a screen for genes that conferred resistance to compression. Myc is also present on chromosome 8, which we found was frequently gained in both our in vitro evolution experiments, and in patient PDAC biopsy samples. We hypothesize that genes and signaling pathways that are crucial for cancer cell survival under compression, will represent new therapeutic targets for solid tumors, especially highly mechanically perturbed tumors like PDAC. We are well positioned to discover these genes by analysis of large numbers of mechanically evolved clones, all of which originated from an isogenic parent. New approaches to treat PDAC are desperately needed. Therefore, the ultimate translation of our research has the potential for significant impact.


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 = $466,008 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	002	7	6/24/2025	NON-COMPETING CONTINUATION	$466,008
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	6	2/26/2025	EXTENSION WITH OR WITHOUT FUNDS	$5
2025	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	5	2/26/2025	NON-COMPETING CONTINUATION	-$5
														Subtotal = $466,008

Issue Date FY: 2024 ( Subtotal = $442,709 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	6	7/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$442,709
														Subtotal = $442,709

Issue Date FY: 2023 ( Subtotal = $456,688 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	5	5/29/2023	NON-COMPETING CONTINUATION	$456,688
2023	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	4	5/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $456,688

Issue Date FY: 2022 ( Subtotal = $466,008 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	4	8/30/2022	NON-COMPETING CONTINUATION	$9,320
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	4	6/22/2022	NON-COMPETING CONTINUATION	$456,688
														Subtotal = $466,008

Issue Date FY: 2021 ( Subtotal = $466,008 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	3	4/20/2021	NON-COMPETING CONTINUATION	$466,008
														Subtotal = $466,008

Issue Date FY: 2020 ( Subtotal = $466,008 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	5/11/2020	NON-COMPETING CONTINUATION	$466,008
														Subtotal = $466,008

Issue Date FY: 2019 ( Subtotal = $466,008 )
2019	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	1	5/31/2019	NEW	$466,008
														Subtotal = $466,008

Grand Total All Awards = $3,229,437

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Cancer under pressure: Mechanisms of adaptation to compressive stress

Award Number: R37CA240765

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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