Tuesday, November 4, 2025 11/4/2025

Instability of Cancer Cell States in Tumor progression (ICCS)

Award Number: R01CA255536
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Instability of Cancer Cell States in Tumor progression (ICCS) - PROJECT SUMMARY ICCS2020-A1 This multi-PI project conducts experiments to study cell state instability in tumor cells, motivated by the theory of “critical transitions” (CT). CTs are abrupt shifts of behavior of a complex non-linear system and are preceded by system state destabilization. A cancer cell population represents a statistical ensemble of cells, each of which is a nonlinear stochastic dynamical system. The latter is embodied by the gene regulatory network (GRN) and cells are normally in stable attractor states. We hypothesize that cancer cells in small lesions can be poised between either staying dormant or exiting dormancy (“escape”) and that this binary decision is a CT. This implies that to be in such a poised state, the cell state has to be destabilized. Thus, detecting cell state instability, manifest in the cell transcriptomes, can discern if a small tumor is safely in a stable state or poised in the above sense. Many an observation suggests that cell density of the dormant tumor may be a “bifurcation parameter” that drives GRN dynamics, via instability toward the CT, at which a cancer cell population can jump to the state of steady growth. SPECIFIC AIMS. The proposed study is experimental but grounded in theory: Cell state instability is manifest in an increase of the quantity IC that we derived from theory and requires single-cell (sc) transcriptomes in a popu- lation to compute (=dynamics of a statistical ensemble of GRNs). Aim 1 (in vitro) uses large ensembles of micro- cultures (=cancer cell populations) to quantitatively show destabilization and bifurcations of growth behaviors. Aim 2 (in vivo) reevaluates old mouse tumor models in a new scheme that exposes the binary decision (dor- mancy vs. “tumor-take”) to test the hypothesis that clinical dormancy escape is preceded by cell state instability. APPROACH: In Aim 1, using massively-parallel micro-cultures, bulk RNASeq and scRNAseq, we examine hith- erto undistinguished growth modes of cancer cells and measure bistability as a function of cell density (dormancy vs. “take-off”). In Aim 2 we examine our intriguing observations in many mouse models: under specific condi- tions, identified by titrating inoculum cell numbers in creating dormant tumors, some mice exhibit stable dor- mancy and others a robust tumor-take despite same initial conditions. This finding suggests a poised state and defines a bistable regime. Tumor models using cells studied in Aim 1 will be evaluated in our scheme to expose bistable behaviors and Ic computed from scRNAseq data. We anticipate that tumors in unstable dormancy poised to take-off display higher cell state instability (higher IC) than the stably dormant tumors. But sc-transcriptomes will also reveal the genes that drive the CT and how they are linked to the risk of impending dormancy escape. SIGNIFICANCE: While this first-in-its-class study analyzes abstract principles rather than specific molecules, its potential impact is tangible: It predicts the fate trajectory of indolent tumors in a new way, complementing current quest for molecular signatures to classify tumors by prognostic groups, by detecting in single-cell resolution cell population data signs of destabilization that herald an approach to the CT or “tipping point” of dormancy escape. This work also raises awareness of non-linear behaviors for the design of more relevant animal tumor models.


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 = $507,800 )
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	002	5	9/4/2025	NON-COMPETING CONTINUATION	$507,800
2025	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	4	10/11/2024	NON-COMPETING CONTINUATION	$8,397
2025	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	4	10/24/2024	NON-COMPETING CONTINUATION	-$8,397
														Subtotal = $507,800

Issue Date FY: 2024 ( Subtotal = $474,027 )
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	4	8/21/2024	NON-COMPETING CONTINUATION	$474,027
														Subtotal = $474,027

Issue Date FY: 2023 ( Subtotal = $486,752 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	3	8/28/2023	NON-COMPETING CONTINUATION	$486,752
														Subtotal = $486,752

Issue Date FY: 2022 ( Subtotal = $479,404 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	2	8/25/2022	NON-COMPETING CONTINUATION	$479,404
2022	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	3/31/2022	NEW	$0
														Subtotal = $479,404

Issue Date FY: 2021 ( Subtotal = $509,003 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	9/21/2021	NEW	$509,003
														Subtotal = $509,003

Grand Total All Awards = $2,456,986

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Instability of Cancer Cell States in Tumor progression (ICCS)

Award Number: R01CA255536

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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