Oncogenic context shapes the fitness landscape of tumor suppression

Lily M. Blair; Joseph M. Juan; Lafia Sebastian; Vy B. Tran; Wensheng Nie; Gregory D. Wall; Mehmet Gerceker; Ian K. Lai; Edwin A. Apilado; Gabriel Grenot; David Amar; Giorgia Foggetti; Mariana Do Carmo; Zeynep Ugur; Debbie Deng; Alex Chenchik; Maria Paz Zafra; Lukas E. Dow; Katerina Politi; Jonathan J. MacQuitty; Dmitri A. Petrov; Monte M. Winslow; Michael J. Rosen; Ian P. Winters

doi:10.1038/s41467-023-42156-y

Oncogenic context shapes the fitness landscape of tumor suppression

Lily M. Blair, Joseph M. Juan, Lafia Sebastian, Vy B. Tran, Wensheng Nie, Gregory D. Wall, Mehmet Gerceker, Ian K. Lai, Edwin A. Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana Do Carmo, Zeynep Ugur, Debbie Deng, Alex Chenchik, Maria Paz Zafra, Lukas E. Dow, Katerina Politi, Jonathan J. MacQuittyDmitri A. Petrov, Monte M. Winslow, Michael J. Rosen^*, Ian P. Winters^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

Original language	English
Article number	6422
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42156-y
State	Published - Dec 2023
Externally published	Yes

Funding

Funders	Funder number
Fundação para a Ciência e a Tecnologia	PTDC/CCI-BIO/29266/2017
National Institutes of Health	R01-CA 234349
NIH SBIR	R44-CA250672

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-023-42156-y

Cite this

Blair, L. M., Juan, J. M., Sebastian, L., Tran, V. B., Nie, W., Wall, G. D., Gerceker, M., Lai, I. K., Apilado, E. A., Grenot, G., Amar, D., Foggetti, G., Do Carmo, M., Ugur, Z., Deng, D., Chenchik, A., Paz Zafra, M., Dow, L. E., Politi, K., ... Winters, I. P. (2023). Oncogenic context shapes the fitness landscape of tumor suppression. Nature Communications, 14(1), Article 6422. https://doi.org/10.1038/s41467-023-42156-y

@article{d641de4abd254050ab35fb26841cee9a,

title = "Oncogenic context shapes the fitness landscape of tumor suppression",

abstract = "Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.",

author = "Blair, {Lily M.} and Juan, {Joseph M.} and Lafia Sebastian and Tran, {Vy B.} and Wensheng Nie and Wall, {Gregory D.} and Mehmet Gerceker and Lai, {Ian K.} and Apilado, {Edwin A.} and Gabriel Grenot and David Amar and Giorgia Foggetti and {Do Carmo}, Mariana and Zeynep Ugur and Debbie Deng and Alex Chenchik and {Paz Zafra}, Maria and Dow, {Lukas E.} and Katerina Politi and MacQuitty, {Jonathan J.} and Petrov, {Dmitri A.} and Winslow, {Monte M.} and Rosen, {Michael J.} and Winters, {Ian P.}",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-42156-y",

language = "אנגלית",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Blair, LM, Juan, JM, Sebastian, L, Tran, VB, Nie, W, Wall, GD, Gerceker, M, Lai, IK, Apilado, EA, Grenot, G, Amar, D, Foggetti, G, Do Carmo, M, Ugur, Z, Deng, D, Chenchik, A, Paz Zafra, M, Dow, LE, Politi, K, MacQuitty, JJ, Petrov, DA, Winslow, MM, Rosen, MJ & Winters, IP 2023, 'Oncogenic context shapes the fitness landscape of tumor suppression', Nature Communications, vol. 14, no. 1, 6422. https://doi.org/10.1038/s41467-023-42156-y

TY - JOUR

T1 - Oncogenic context shapes the fitness landscape of tumor suppression

AU - Blair, Lily M.

AU - Juan, Joseph M.

AU - Sebastian, Lafia

AU - Tran, Vy B.

AU - Nie, Wensheng

AU - Wall, Gregory D.

AU - Gerceker, Mehmet

AU - Lai, Ian K.

AU - Apilado, Edwin A.

AU - Grenot, Gabriel

AU - Amar, David

AU - Foggetti, Giorgia

AU - Do Carmo, Mariana

AU - Ugur, Zeynep

AU - Deng, Debbie

AU - Chenchik, Alex

AU - Paz Zafra, Maria

AU - Dow, Lukas E.

AU - Politi, Katerina

AU - MacQuitty, Jonathan J.

AU - Petrov, Dmitri A.

AU - Winslow, Monte M.

AU - Rosen, Michael J.

AU - Winters, Ian P.

PY - 2023/12

Y1 - 2023/12

N2 - Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

AB - Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

UR - http://www.scopus.com/inward/record.url?scp=85174159936&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-42156-y

DO - 10.1038/s41467-023-42156-y

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 37828026

AN - SCOPUS:85174159936

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6422

ER -

Oncogenic context shapes the fitness landscape of tumor suppression

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this