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Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
Open accessPublished version of a preprint
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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“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
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In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“Specifically, HDAC5 suppresses SOCS3, boosting CCL2 and CCL7 expression.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Self-citationThe Cancer-Immune Set Point in Oesophageal Cancer
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Self-citation
Metadata
- 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
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