La transición dinámica entre estados celulares impulsados por MAPK y estados celulares impulsados por WNT impulsa el cáncer intestinal y determina la respuesta al tratamiento.

AbstractColorectal cancer (CRC) frequently harbors activating mutations in the WNT and MAPK pathways. While KRAS mutations alone can drive tumor initiation in many tissues, they are insufficient in the intestine. Leveraging allele-specific properties of RAS, we developed a mouse model to investigate MAPK hyperactivation. Here we show that KRAS mutations drive a regenerative state while antagonizing the Lgr5+ intestinal stem cell state; however, this regenerative state cannot initiate tumorigenesis. Instead, tumor initiation requires a stem-like state dependent on mutational activation of the WNT pathway. We identify two aberrant states—a WNT-driven stem-like state for tumor initiation and MAPK-driven transit-amplifying-like state for tumor growth. These plastic states, essential for tumorigenesis, also impact drug response, potentially explaining lower response rates and shorter duration of response to KRAS-G12C inhibitors in CRC compared to non-small cell lung cancer. These findings highlight the need to target both pathways and their associated cell states for effective CRC treatment.

Access through your institution







Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: KRAS hyperactivation depletes Lgr5+ ISCs.The alternative text for this image may have been generated using AI.Fig. 2: Elevated MAPK output induces a plastic regenerative state.The alternative text for this image may have been generated using AI.Fig. 3: WNT activating mutations are required for intestinal tumor initiation.The alternative text for this image may have been generated using AI.Fig. 4: WNT pathway activation maintains Lgr5+ ISCs, allowing tumor initiation.The alternative text for this image may have been generated using AI.Fig. 5: WNT and RAS/MAPK define two distinct but plastic states.The alternative text for this image may have been generated using AI.Fig. 6: Plasticity between the WNT and RAS/MAPK states shapes drug response.The alternative text for this image may have been generated using AI.

Similar content being viewed by others









A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer



Article

07 May 2026












Colon cancer cells evade drug action by enhancing drug metabolism



Article
Open access
10 July 2025












MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance



Article
Open access
24 November 2025

Data availability

Sequencing data have been deposited in the GEO public repository under accessions GSE301556, GSE301559, GSE301561, GSE301565, GSE301567, GSE301568, GSE301970, GSE301967 and GSE303719. The data that support the real-world data findings of this study were originated by, and are the property of, Flatiron Health and Foundation Medicine, which have restrictions prohibiting the authors from making the dataset publicly available. Requests for data sharing by license or by permission for the specific purpose of replicating results in this paper can be submitted to PublicationsDataaccess@flatiron.com and cgdb-fmi@flatiron.com. Access to the data is typically managed through a proposal-based process, where researchers must outline the intended use of the data for review by Flatiron Health and/or Foundation Medicine. Access requires establishing a data use agreement (or similar contractual arrangement) to ensure appropriate data handling and compliance with privacy regulations. As this is a licensed dataset, access may involve fees, depending on the scope and nature of the request. Flatiron Health/Foundation Medicine determines the time frame for access, which may vary depending on the review and contracting process. Data used from publicly available sources includes GSE214821. Source data are provided with this paper. Requests for plasmids, mouse organoid models, KrasLSL-Q61R mice and other reagents generated in this study will be available upon request. These materials will be distributed by Genentech upon completion of the materials transfer agreement.
Code availability

No custom code was generated in this study. All analyses were performed using publicly available software packages as cited in Methods.
ReferencesSiegel, R. L., Wagle, N. S., Cercek, A., Smith, R. A. & Jemal, A. Colorectal cancer statistics, 2023. CA Cancer J. Clin. 73, 233–254 (2023).PubMed 

Google Scholar 
Sinicrope, F. A. Increasing incidence of early-onset colorectal cancer. N. Engl. J. Med. 386, 1547–1558 (2022).CAS 
PubMed 

Google Scholar 
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Google Scholar 
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).CAS 
PubMed 

Google Scholar 
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).CAS 
PubMed 

Google Scholar 
Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).CAS 
PubMed 

Google Scholar 
Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014).CAS 
PubMed 

Google Scholar 
Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40, 600–608 (2008).CAS 
PubMed 
PubMed Central 

Google Scholar 
Najumudeen, A. K. et al. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo. Nat. Commun. 15, 100 (2024).CAS 
PubMed 
PubMed Central 

Google Scholar 
Feng, Y. et al. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology 141, 1003–1013 (2011).CAS 
PubMed 
PubMed Central 

Google Scholar 
Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122–14127 (2006).CAS 
PubMed 
PubMed Central 

Google Scholar 
Janssen, K. P. et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131, 1096–1099 (2006).CAS 
PubMed 

Google Scholar 
Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).CAS 
PubMed 
PubMed Central 

Google Scholar 
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Google Scholar 
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).CAS 
PubMed 

Google Scholar 
Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged?. Nat. Rev. Drug Discov. 19, 533–552 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).CAS 
PubMed 

Google Scholar 
Smith, M. J., Neel, B. G. & Ikura, M. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc. Natl Acad. Sci. USA 110, 4574–4579 (2013).CAS 
PubMed 
PubMed Central 

Google Scholar 
El Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004).CAS 
PubMed 

Google Scholar 
Poulin, E. J. et al. Tissue-specific oncogenic activity of KRASA146T. Cancer Discov. 9, 738–755 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
Johnson, C. W. et al. Isoform-specific destabilization of the active site reveals a molecular mechanism of intrinsic activation of KRas G13D. Cell Rep. 28, 1538–1550 (2019).PubMed 
PubMed Central 

Google Scholar 
Zafra, M. P. et al. An in vivo Kras allelic series reveals distinct phenotypes of common oncogenic variants. Cancer Discov. 10, 1654–1671 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Van Es, J. H. et al. A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal. Mol. Cell. Biol. 32, 1918–1927 (2012).PubMed 
PubMed Central 

Google Scholar 
Van der Flier, L. G., Haegebarth, A., Stange, D. E., van de Wetering, M. & Clevers, H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).PubMed 

Google Scholar 
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).CAS 
PubMed 

Google Scholar 
Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).CAS 
PubMed 
PubMed Central 

Google Scholar 
Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).CAS 
PubMed 
PubMed Central 

Google Scholar 
Singh, P. N. P., Madha, S., Leiter, A. B. & Shivdasani, R. A. Cell and chromatin transitions in intestinal stem cell regeneration. Genes Dev. 36, 684–698 (2022).CAS 
PubMed 
PubMed Central 

Google Scholar 
Nazaret, A. et al. Joint representation and visualization of derailed cell states with Decipher. Genome Biol. 26, 219 (2025).PubMed 
PubMed Central 

Google Scholar 
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
Burdziak, C. et al. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis. Science 380, eadd5327 (2023).CAS 
PubMed 
PubMed Central 

Google Scholar 
DeTomaso, D. & Yosef, N. Hotspot identifies informative gene modules across modalities of single-cell genomics. Cell Syst. 12, 446–456 (2021).CAS 
PubMed 

Google Scholar 
Mustata, R. C. et al. Identification of Lgr5-independent spheroid-generating progenitors of the mouse fetal intestinal epithelium. Cell Rep. 5, 421–432 (2013).CAS 
PubMed 

Google Scholar 
Leach, J. D. G. et al. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat. Commun. 12, 3464 (2021).CAS 
PubMed 
PubMed Central 

Google Scholar 
Nusse, Y. M. et al. Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
Deng, T. & Karin, M. c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK. Nature 371, 171–175 (1994).CAS 
PubMed 

Google Scholar 
Dey, A., Varelas, X. & Guan, K. L. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat. Rev. Drug Discov. 19, 480–494 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 526, 715–718 (2015).CAS 
PubMed 

Google Scholar 
Ayyaz, A. et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569, 121–125 (2019).CAS 
PubMed 

Google Scholar 
De Sousa, E. M. F. & de Sauvage, F. J. Cellular plasticity in intestinal homeostasis and disease. Cell Stem Cell 24, 54–64 (2019).
Google Scholar 
Wang, P. et al. Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells. Cell Stem Cell 30, 1166–1178 (2023).CAS 
PubMed 

Google Scholar 
Sinha, A., Nightingale, J., West, K. P., Berlanga-Acosta, J. & Playford, R. J. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N. Engl. J. Med. 349, 350–357 (2003).CAS 
PubMed 

Google Scholar 
Jarde, T. et al. Mesenchymal niche-derived neuregulin-1 drives intestinal stem cell proliferation and regeneration of damaged epithelium. Cell Stem Cell 27, 646–662 (2020).CAS 
PubMed 

Google Scholar 
Dar, M. S., Singh, P., Mir, R. A. & Dar, M. J. β-catenin N-terminal domain: an enigmatic region prone to cancer causing mutations. Mutat. Res. Rev. Mutat. Res. 773, 122–133 (2017).CAS 
PubMed 

Google Scholar 
Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nat. Genet. 21, 410–413 (1999).CAS 
PubMed 

Google Scholar 
Kuraguchi, M. et al. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet. 2, e146 (2006).PubMed 
PubMed Central 

Google Scholar 
Kuraguchi, M., Ohene-Baah, N. Y., Sonkin, D., Bronson, R. T. & Kucherlapati, R. Genetic mechanisms in Apc-mediated mammary tumorigenesis. PLoS Genet. 5, e1000367 (2009).PubMed 
PubMed Central 

Google Scholar 
De Sousa e Melo, F. et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).PubMed 

Google Scholar 
Shimokawa, M. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017).CAS 
PubMed 

Google Scholar 
Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).CAS 
PubMed 

Google Scholar 
Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).CAS 
PubMed 

Google Scholar 
Zorn, A. M. et al. Regulation of Wnt signaling by Sox proteins: XSox17 α/β and XSox3 physically interact with β-catenin. Mol. Cell 4, 487–498 (1999).CAS 
PubMed 

Google Scholar 
Becker, W. R. et al. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer. Nat. Genet. 54, 985–995 (2022).CAS 
PubMed 
PubMed Central 

Google Scholar 
Purkey, H. Abstract ND11: discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Cancer Res. 82, ND11 (2022).
Google Scholar 
Hagenbeek, T. J. et al. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance. Nat. Cancer 4, 812–828 (2023).CAS 
PubMed 
PubMed Central 

Google Scholar 
Hallin, J. et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat. Med. 28, 2171–2182 (2022).CAS 
PubMed 

Google Scholar 
Quintanal-Villalonga, A. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 17, 360–371 (2020).PubMed 
PubMed Central 

Google Scholar 
Romero, R. et al. The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1. Nat. Cancer 5, 1641–1659 (2024).CAS 
PubMed 
PubMed Central 

Google Scholar 
Rubin, M. A., Bristow, R. G., Thienger, P. D., Dive, C. & Imielinski, M. Impact of lineage plasticity to and from a neuroendocrine phenotype on progression and response in prostate and lung cancers. Mol. Cell 80, 562–577 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5, 341–354 (2005).CAS 
PubMed 

Google Scholar 
Bala, P. et al. Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation. Sci. Adv. 9, eadf0927 (2023).CAS 
PubMed 
PubMed Central 

Google Scholar 
Huynh, M. V. et al. Functional and biological heterogeneity of KRASQ61 mutations. Sci. Signal. 15, eabn2694 (2022).CAS 
PubMed 
PubMed Central 

Google Scholar 
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J. & Haigis, K. M. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat. Commun. 12, 1808 (2021).CAS 
PubMed 
PubMed Central 

Google Scholar 
Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
Zhan, T. et al. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer. Nat. Commun. 10, 2197 (2019).PubMed 
PubMed Central 

Google Scholar 
Kabiri, Z. et al. Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells. J. Clin. Invest. 128, 3806–3812 (2018).PubMed 
PubMed Central 

Google Scholar 
Sun, X., Wu, L. F., Altschuler, S. J. & Hata, A. N. Targeting therapy-persistent residual disease. Nat. Cancer 5, 1298–1304 (2024).PubMed 
PubMed Central 

Google Scholar 
Hong, D. S. et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Janne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N. Engl. J. Med. 387, 120–131 (2022).CAS 
PubMed 

Google Scholar 
Sacher, A. et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N. Engl. J. Med. 389, 710–721 (2023).CAS 
PubMed 

Google Scholar 
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).PubMed 
PubMed Central 

Google Scholar 
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).PubMed 
PubMed Central 

Google Scholar 
Seibler, J. et al. Rapid generation of inducible mouse mutants. Nucleic Acids Res. 31, e12 (2003).PubMed 
PubMed Central 

Google Scholar 
Blanpain, C., Mohrin, M., Sotiropoulou, P. A. & Passegue, E. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell 8, 16–29 (2011).CAS 
PubMed 

Google Scholar 
Booth, C., Tudor, G., Tudor, J., Katz, B. P. & MacVittie, T. J. Acute gastrointestinal syndrome in high-dose irradiated mice. Health Phys. 103, 383–399 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
Taraborrelli, L. et al. Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer. Nat. Commun. 14, 5945 (2023).CAS 
PubMed 
PubMed Central 

Google Scholar 
Regier, A. A. et al. Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects. Nat. Commun. 9, 4038 (2018).PubMed 
PubMed Central 

Google Scholar 
Ross-Innes, C. S. et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481, 389–393 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).CAS 
PubMed 
PubMed Central 

Google Scholar 
Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
Traag, V. A., Waltman, L. & van Eck, N. J. From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 9, 5233 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
Cao, Z. J. & Gao, G. Multi-omics single-cell data integration and regulatory inference with graph-linked embedding. Nat. Biotechnol. 40, 1458–1466 (2022).CAS 
PubMed 
PubMed Central 

Google Scholar 
Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163–172 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
Fornes, O. et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48, D87–D92 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
Wlodarczyk, T. et al. Epiregulon: single-cell transcription factor activity inference to predict drug response and drivers of cell states. Nat. Commun. 16, 7118 (2025).CAS 
PubMed 
PubMed Central 

Google Scholar 
Persad, S. et al. SEACells infers transcriptional and epigenomic cellular states from single-cell genomics data. Nat. Biotechnol. 41, 1746–1757 (2023).CAS 
PubMed 
PubMed Central 

Google Scholar 
Download referencesAcknowledgementsWe would like to thank A. Castillo and T. Chen for their assistance with mouse colony management, the Genetically Engineered Mouse Models laboratory for constructing the KrasLSL-Q61R allele, the necropsy team for necropsy support, the Pathology Core for help with histology and the NGS laboratory for RNA-seq, WES, snRNA-seq, scATAC–seq and ATAC–seq. We would also like to thank the members of the de Sauvage lab for their insightful discussions.Author informationAuthors and AffiliationsDepartment of Research Oncology, Genentech, South San Francisco, CA, USAAmanda R. Moore, Brian Biehs, Noelyn Kljavin, Akansha Shah, Jeremy Burton, Honglin Jiang, Deepankar Chakroborty, Weilan Ye, Sandra P. Melo & Frederic J. de SauvageDepartment of Discovery Oncology, Genentech, South San Francisco, CA, USAAmanda R. Moore, Jenille Tan, Xin Ye, Kamakoti P. Bhat, Shiqi Xie & Shiva MalekComputational Sciences Center of Excellence, Genentech, South San Francisco, CA, USAThi Thu Thao Nguyen, Dongze He & Sandra P. MeloDepartment of Real World Data Science, Genentech, South San Francisco, CA, USALisa Wang & Nayan ChaudharyDepartment of Research Pathology, Genentech, South San Francisco, CA, USAWilliam Lin, Kathryn Mesh, Lisa Tai & Lisa McGinnisDepartment of Cellular and Tissue Genomics, Genentech, South San Francisco, CA, USALisa McGinnisAuthorsAmanda R. MooreView author publicationsSearch author on:PubMed Google ScholarBrian BiehsView author publicationsSearch author on:PubMed Google ScholarNoelyn KljavinView author publicationsSearch author on:PubMed Google ScholarThi Thu Thao NguyenView author publicationsSearch author on:PubMed Google ScholarAkansha ShahView author publicationsSearch author on:PubMed Google ScholarJeremy BurtonView author publicationsSearch author on:PubMed Google ScholarHonglin JiangView author publicationsSearch author on:PubMed Google ScholarJenille TanView author publicationsSearch author on:PubMed Google ScholarDeepankar ChakrobortyView author publicationsSearch author on:PubMed Google ScholarLisa WangView author publicationsSearch author on:PubMed Google ScholarNayan ChaudharyView author publicationsSearch author on:PubMed Google ScholarDongze HeView author publicationsSearch author on:PubMed Google ScholarWilliam LinView author publicationsSearch author on:PubMed Google ScholarKathryn MeshView author publicationsSearch author on:PubMed Google ScholarXin YeView author publicationsSearch author on:PubMed Google ScholarKamakoti P. BhatView author publicationsSearch author on:PubMed Google ScholarLisa TaiView author publicationsSearch author on:PubMed Google ScholarShiqi XieView author publicationsSearch author on:PubMed Google ScholarWeilan YeView author publicationsSearch author on:PubMed Google ScholarLisa McGinnisView author publicationsSearch author on:PubMed Google ScholarShiva MalekView author publicationsSearch author on:PubMed Google ScholarSandra P. MeloView author publicationsSearch author on:PubMed Google ScholarFrederic J. de SauvageView author publicationsSearch author on:PubMed Google ScholarContributionsF.J.d.S. and S.M. supervised the study. A.R.M., S.M., S.P.M. and F.J.d.S. designed and planned the study. A.R.M., S.P.M. and F.J.d.S. wrote the paper. S.P.M. conducted the bioinformatics analyses. A.R.M., B.B., N.K., T.T.T.N., A.S., J.B., H.J., J.T., D.C., L.W., N.C., D.H., W.L., K.M., X.Y., K.P.B., L.T., S.X., W.Y. and L.M. performed experiments, interpreted data and discussed results.Corresponding authorsCorrespondence to
Sandra P. Melo or Frederic J. de Sauvage.Ethics declarations

Competing interests
All authors are employed by Genentech or were employed by Genentech at the time of their contributions to the work.

Peer review


Peer review information
Nature Genetics thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 KRAS hyperactivation drives enhanced proliferation.a, Schematic representation of the KrasLSL-Q61R conditional knock-in allele with primer (P1–P3) sites indicated. b, Recombination of KrasLSL-G12D and KrasLSL-Q61R alleles. Representative gel showing recombination 10 days post-tamoxifen induction. Bands at 650 bp and 343 bp correspond to recombined KrasG12D and KrasQ16R, respectively. n = 3 mice. c,d, MAPK pathway activation assessed by western blot (c) and gene expression analysis (d), showing the relative expression of negative regulators of the MAPK pathway in small intestinal tissue from Rosa26CreER; Kras+/+, Rosa26CreER; KrasG12D, and Rosa26CreER; KrasQ61R mice, collected 10 days post-tamoxifen induction. Bulk RNA-seq data were normalized as described in the Methods, and differential expression analysis was performed using voom-transformed counts and linear modeling with moderated t-tests (two-sided). P-values were adjusted for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method. n = 3 mice per genotype. *P