Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
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Abstract
Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53−/− PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. Significance: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components. See related commentary by Carr and Fernandez-Zapico, p. 910. This article is highlighted in the In This Issue feature, p. 890
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KRAS G12D boosts GM-CSF production in PDAC cancer cells, thereby attracting immunosuppressive myeloid cells that can dampen the activity of CD8 T-cells.
“This discovery gains significance considering the ability of KRAS G12D to boost GM-CSF production in PDAC cancer cells, thereby attracting immunosuppressive myeloid cells that can dampen the activity of CD8 T-cells [54].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
The Introduction (page unavailable) says oncogenic KRAS stimulates GM-CSF production in PDAC cancer cells, recruiting myeloid cells that suppress CD8+ T-cell function. It does not specify that this effect is attributable to the G12D variant, so the allele-specific part of the claim is not established by our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredYAP can restore oncogenicity in murine tumors that have lost KRAS.
“YAP, a pivotal EMT regulator gene, can restore oncogenicity in murine tumors that have lost KRAS [54,131].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
In HDAC5-rich tumors, macrophages increase TGFβ production, triggering pSMAD3/SMAD4 signaling in cancer cells and bypassing the need for KRAS.
“In HDAC5-rich tumors, these macrophages increase TGFβ production, triggering pSMAD3/SMAD4 signaling in cancer cells, and bypassing the need for KRAS.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
HDAC5 suppresses SOCS3, boosting CCL2 and CCL7 expression.
“Specifically, HDAC5 suppresses SOCS3, boosting CCL2 and CCL7 expression.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
Gain-of-function screens identified HDAC5 as a driver of resistance to KRAS inhibition within the tumor microenvironment.
“Gain-of-function screens of epigenetic regulators in KRAS-mutant PDAC models identified HDAC5 as a driver of resistance to KRAS inhibition within the tumor microenvironment [54].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
Studies of the iKras mouse model have highlighted mechanisms to enable bypass of oncogenic KRAS addiction, including adoption of a KRAS-independent cell state dependent on oxidative phosphorylation, induction of SMARCB-MYC-network-driven mesenchymal reprogramming, activation of the TGFβ-SMAD3/4 axis via TME remodeling, and USP21-mediated upregulation of macropinocytosis.
“Furthermore, studies of the iKras mouse model have highlighted myriad mechanisms to enable bypass of oncogenic KRAS addiction, including the adoption of a KRAS-independent cell state dependent on oxidative phosphorylation (5), induction of SMARCB–MYC-network-driven mesenchymal reprogramming (38), activation of the TGFβ-SMAD3/4 axis via TME remodeling (39), and USP21-mediated upregulation of macrop”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [39]
In KRASG12D-driven PDAC mouse models, immune suppressive cytokines IL-4 and IL-13 and remodeling of myeloid cell composition in the tumor microenvironment have been demonstrated.
“In a KRASG12D mutation driven PDAC mice model, immune suppressive cytokines IL-4 and IL-13 and remodeling of the myeloid cell composition in TME have been demonstrated40,41.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [40]
Overexpression of histone deacetylase HDAC5 enables bypass of KRAS extinguishment through cytokine-mediated remodeling of the tumor microenvironment.
“Overexpression of the histone deacetylase HDAC5 also enables bypass of KRAS extinguishment through cytokine-mediate remodeling of the tumor microenvironment (86).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [86]
Inhibitors of the HDAC5-SMAD4 pathways in combination with KRAS (G12D) inhibition have synergistic antitumor effects in an isogenic PDAC model.
“Inhibitors of the HDAC5-SMAD4 pathways in combination with KRAS (G12D) inhibition have synergistic antitumor effects in an isogenic PDAC model [146].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [146]
These tumor-associated macrophages (TAMs) provide cancer cells with TGFβ that promotes KRAS mutation-independent PDAC cell growth after KRAS mutation-targeted inhibition.
“These tumor-associated macrophages (TAMs) provide cancer cells with TGFβ that promotes KRAS mutation-independent PDAC cell growth after KRAS mutation-targeted inhibition.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [146]
Histone deacetylase 5 (HDAC5)-induced bypass promotes macrophage recruitment into the TME and enables tumor recurrence following the extinction of KRAS (G12D).
“Histone deacetylase 5 (HDAC5)-induced bypass promotes macrophage recruitment into the TME and enables tumor recurrence following the extinction of KRAS (G12D) [146].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [146]
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- Authors
- Hou, P., Kapoor, A., Zhang, Q., Li, J., Wu, C.-J., Li, J., Lan, Z., Tang, M., Ma, X., Ackroyd, J. J., Kalluri, R., Zhang, J., Jiang, S., Spring, D. J., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Wang, Y. Alan
- DePinho, Ronald A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-07-01
- Volume
- 10
- Issue
- 7
- Pages
- 1058-1077
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7334087
- OpenAlex
- W3019483263
- Cited by
- 154
- References
- 57
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 29 · 2023: 30 · 2022: 26 · 2021: 25 · 2020: 7
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P30 CA016672, P01 CA117969, R01 CA225955, R01 CA231349)
- Hirshberg Foundation for Pancreatic Cancer Research
- Emerson Collective
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic ductal adenocarcinoma, KRAS, tumor microenvironment, HDAC5, epigenetic regulators, tumor-associated macrophages, MCP-1, CCR2, SOCS3, TGF-beta, SMAD4, tumor recurrence
- MeSH terms
- Humans, Oncogenes, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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